1
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Yang D, Sun W, Gao L, Zhao K, Zhuang Q, Cai Y. Cell competition as an emerging mechanism and therapeutic target in cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167769. [PMID: 40054587 DOI: 10.1016/j.bbadis.2025.167769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/18/2025] [Accepted: 02/27/2025] [Indexed: 03/17/2025]
Abstract
Cell competition, as an internal quality control mechanism that constantly monitor cell fitness and eliminate unfit cells, maintains proper embryogenesis and tissue integrity during early development and adult homeostasis. Recent studies have revealed that cell competition functions as a tumor-suppressive mechanism to defend against cancer by removing neoplastic cell, which however, is hijacked by tumor cells and drive cell competition in favor of mutant cells, thereby promoting cancer initiation and progression. In this review, with a special focus on mammalian systems, we discuss the latest insights into the mechanisms regulating cell competition and its dual role in tumor development. We also provide current strategies to modulate the direction of cell competition for the prevention and treatment of cancers.
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Affiliation(s)
- Dakai Yang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
| | - Wenyue Sun
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Lu Gao
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Kai Zhao
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China
| | - Qin Zhuang
- Department of General Practice, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
| | - Yun Cai
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China.
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2
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Weijers DD, Hinić S, Kroeze E, Gorris MA, Schreibelt G, Middelkamp S, Mensenkamp AR, Bladergroen R, Verrijp K, Hoogerbrugge N, Wesseling P, van der Post RS, Loeffen JL, Gidding CE, van Kouwen MC, de Vries IJM, van Boxtel R, de Voer RM, Jongmans MC, Kuiper RP. Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency. Nat Commun 2025; 16:4459. [PMID: 40368937 PMCID: PMC12078508 DOI: 10.1038/s41467-025-59775-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 05/05/2025] [Indexed: 05/16/2025] Open
Abstract
Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in mismatch repair (MMR) genes, is associated with high cancer incidence early in life. A better understanding of mutational processes driving sequential CMMRD tumors can advance optimal treatment. Here, we describe a genomic characterization on a representative collection of CMMRD-associated tumors consisting of 41 tumors from 17 individuals. Mutational patterns in these tumors appear to be influenced by multiple factors, including the affected MMR gene and tumor type. Somatic polymerase proofreading mutations, commonly present in brain tumors, are also found in a T-cell lymphoblastic lymphoma displaying associated mutational patterns. We show prominent mutational patterns in two second primary hematological malignancies after temozolomide treatment. Furthermore, an indel signature, characterized by one-base pair cytosine insertions in cytosine homopolymers, is found in 54% of tumors. In conclusion, analysis of sequential CMMRD tumors reveals diverse mutational patterns influenced by the affected MMR gene, tumor type and treatment history.
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Affiliation(s)
- Dilys D Weijers
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Snežana Hinić
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
| | - Emma Kroeze
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Mark Aj Gorris
- Department of Medical BioSciences, Radboud university medical center, Nijmegen, The Netherlands
- Division of Immunotherapy, Oncode Institute, Radboud university medical center, Nijmegen, The Netherlands
| | - Gerty Schreibelt
- Department of Medical BioSciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Sjors Middelkamp
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Arjen R Mensenkamp
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
| | - Reno Bladergroen
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Kiek Verrijp
- Department of Medical BioSciences, Radboud university medical center, Nijmegen, The Netherlands
- Division of Immunotherapy, Oncode Institute, Radboud university medical center, Nijmegen, The Netherlands
- Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
| | - Pieter Wesseling
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands
| | - Rachel S van der Post
- Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands
| | - Jan Lc Loeffen
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Corrie Em Gidding
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Mariëtte Ca van Kouwen
- Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, The Netherlands
| | - I Jolanda M de Vries
- Department of Medical BioSciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Ruben van Boxtel
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Richarda M de Voer
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
| | - Marjolijn Cj Jongmans
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roland P Kuiper
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
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3
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Abeysundara N, Rasnitsyn A, Fong V, Bahcheli A, Van Ommeren R, Juraschka K, Vladoiu M, Ong W, Livingston B, de Antonellis P, Ly M, Holgado BL, Sirbu O, Bahrampour S, Min HK, Fan J, Nor C, Visvanathan A, Zhang J, Wang H, Qin L, Huang N, Pallotta J, Douglas T, Mak E, Su H, Ng K, Zhang KY, Daniels C, Lucas CHG, Eberhart CG, Liu H, Jiang T, Notta F, Ramaswamy V, Reimand J, Gallo M, Rich JN, Wu X, Huang X, Taylor MD. Metastatic medulloblastoma remodels the local leptomeningeal microenvironment to promote further metastatic colonization and growth. Nat Cell Biol 2025; 27:863-874. [PMID: 40263572 PMCID: PMC12081294 DOI: 10.1038/s41556-025-01660-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 03/25/2025] [Indexed: 04/24/2025]
Abstract
Leptomeningeal metastases are the major source of morbidity and mortality for patients with medulloblastoma. The biology of the leptomeningeal metastases and the local tumour microenvironment are poorly characterized. Here we show that metastasis-associated meningeal fibroblasts (MB-MAFs) are transcriptionally distinct and signal extensively to tumour cells and the tumour microenvironment. Metastatic cells secrete platelet-derived growth factor (PDGF) ligands into the local microenvironment to chemotactically recruit meningeal fibroblasts. Meningeal fibroblasts are reprogrammed to become MB-MAFs, expressing distinct transcriptomes and secretomes, including bone morphogenetic proteins. Active bone morphogenetic protein signalling and co-implantation of tumour cells with MB-MAFs enhances the colonization of the leptomeninges by medulloblastoma cells and promotes the growth of established metastases. Furthermore, treatment of patient-derived xenograft mice with a PDGF-receptor-α neutralizing antibody enhances overall survival in vivo. Collectively, our results define a targetable intercellular communication cascade in the metastatic niche to treat leptomeningeal disease.
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Affiliation(s)
- Namal Abeysundara
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Alexandra Rasnitsyn
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Vernon Fong
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Alexander Bahcheli
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Randy Van Ommeren
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Kyle Juraschka
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Maria Vladoiu
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Winnie Ong
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Bryn Livingston
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Pasqualino de Antonellis
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Michelle Ly
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Borja López Holgado
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Olga Sirbu
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Shahrzad Bahrampour
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Hyun-Kee Min
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Jerry Fan
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Carolina Nor
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Abhirami Visvanathan
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jiao Zhang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Texas Children's Cancer and Hematology Center, Houston, TX, USA
- Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Hao Wang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lei Qin
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Ning Huang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jonelle Pallotta
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Tajana Douglas
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Esta Mak
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Haipeng Su
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Karen Ng
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Kevin Yang Zhang
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Craig Daniels
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Texas Children's Cancer and Hematology Center, Houston, TX, USA
- Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
| | | | - Charles G Eberhart
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Hailong Liu
- Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tao Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Faiyaz Notta
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Vijay Ramaswamy
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Jüri Reimand
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Marco Gallo
- Texas Children's Cancer and Hematology Center, Houston, TX, USA
- Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Jeremy N Rich
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
| | - Xiaochong Wu
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Texas Children's Cancer and Hematology Center, Houston, TX, USA
- Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Xi Huang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Michael D Taylor
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
- Texas Children's Cancer and Hematology Center, Houston, TX, USA.
- Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
- Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
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4
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Li YZ, Gao L, Sun XL, Duan L, Jiang M, Wu QF. Neural cell competition sculpting brain from cradle to grave. Natl Sci Rev 2025; 12:nwaf057. [PMID: 40309342 PMCID: PMC12042753 DOI: 10.1093/nsr/nwaf057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/18/2025] [Accepted: 02/13/2025] [Indexed: 05/02/2025] Open
Abstract
Darwinian selection, operating within the cellular ecosystem of multicellular organisms, drives a pervasive surveillance mechanism of cell-cell competition that shapes tissue architecture and function. While cell competition eliminates suboptimal cells to ensure tissue integrity across various tissues, neuronal competition specifically sculpts neural networks to establish precise circuits for sensory, motor and cognitive functions. However, our understanding of cell competition across diverse neural cell types in both developmental and pathological contexts remains limited. Here, we review recent advances on the phenomenon, and mechanisms and potential functions of neural cell competition (NCC), ranging from neural progenitors, neurons, astrocytes and oligodendrocytes to microglia. Physiological NCC governs cellular survival, proliferation, arborization, organization, function and territorial colonization, whereas dysregulated NCC may cause neurodevelopmental disorders, accelerate aging, exacerbate neurodegenerative diseases and drive brain tumor progression. Future work that leverages cell competition mechanisms may help to improve cognition and curb diseases.
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Affiliation(s)
- Yu Zheng Li
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Lisen Gao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xue-Lian Sun
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
| | - Lihui Duan
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Man Jiang
- Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qing-Feng Wu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100101, China
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Children's Hospital, Beijing 100045, China
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5
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Huang S, Soto AM, Sonnenschein C. The end of the genetic paradigm of cancer. PLoS Biol 2025; 23:e3003052. [PMID: 40100793 DOI: 10.1371/journal.pbio.3003052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025] Open
Abstract
Genome sequencing of cancer and normal tissues, alongside single-cell transcriptomics, continues to produce findings that challenge the idea that cancer is a 'genetic disease', as posited by the somatic mutation theory (SMT). In this prevailing paradigm, tumorigenesis is caused by cancer-driving somatic mutations and clonal expansion. However, results from tumor sequencing, motivated by the genetic paradigm itself, create apparent 'paradoxes' that are not conducive to a pure SMT. But beyond genetic causation, the new results lend credence to old ideas from organismal biology. To resolve inconsistencies between the genetic paradigm of cancer and biological reality, we must complement deep sequencing with deep thinking: embrace formal theory and historicity of biological entities, and (re)consider non-genetic plasticity of cells and tissues. In this Essay, we discuss the concepts of cell state dynamics and tissue fields that emerge from the collective action of genes and of cells in their morphogenetic context, respectively, and how they help explain inconsistencies in the data in the context of SMT.
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Affiliation(s)
- Sui Huang
- Institute for Systems Biology, Seattle, Washington, United States of America
| | - Ana M Soto
- Tufts University School of Medicine, Immunology, Boston, Massachusetts, United States of America
| | - Carlos Sonnenschein
- Tufts University School of Medicine, Immunology, Boston, Massachusetts, United States of America
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6
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Jiang Z, Allkanjari MS, Chung PED, Tran H, Ghanbari-Azarnier R, Wang DY, Lin DJ, Min JY, Ben-David Y, Zacksenhaus E. Recent Advances in Pineoblastoma Research: Molecular Classification, Modelling and Targetable Vulnerabilities. Cancers (Basel) 2025; 17:720. [PMID: 40075567 PMCID: PMC11898778 DOI: 10.3390/cancers17050720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/17/2025] [Accepted: 02/17/2025] [Indexed: 03/14/2025] Open
Abstract
Pineoblastoma (PB) is a rare yet lethal pediatric brain cancer of the pineal gland, a small endocrine organ that secretes melatonin to regulate the circadian rhythm. For PB patients ≤5 years of age, the overall survival rate is approximately 15%; metastatic PB is incurable. Standard treatment, including surgical resection, radiation, and systemic chemotherapy, improves survival but compromises neurocognitive function. A better understanding of the disease and the generation of preclinical models may enable re-evaluation of previous clinical trials, development of precision therapeutic strategies and improve patient outcome. Over the past 5 years, PB has been recognized to include several major subtypes driven by (i) loss of microRNA processing factors DICER and DROSHA characterized by a relatively good prognosis; (ii) loss of the retinoblastoma tumor suppressor RB1; and (iii) amplification or induction of the cMYC protooncogene, with the latter two subtypes exhibiting exceedingly poor prognosis. Recently, mouse models for the major PB subtypes (RB1-, DICER1- and DROSHA-) except MYC- have been established. This progress, including better understanding of the disease, cell of origin, tumor progression, role of autophagy, and targetable vulnerabilities, holds promise for novel therapeutic strategies to combat each subtype of this lethal childhood malignancy.
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Affiliation(s)
- Zhe Jiang
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Michelle S. Allkanjari
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Philip E. D. Chung
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Hanna Tran
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Ronak Ghanbari-Azarnier
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Dong-Yu Wang
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Daniel J. Lin
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Jung Yeon Min
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
| | - Yaacov Ben-David
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
- Natural Products Research Center of Guizhou Province, Guiyang 550004, China
| | - Eldad Zacksenhaus
- Toronto General Research Institute, University Health Network, 101 College Street, Max Bell Research Centre, Suite 5R406, Toronto, ON M5G 1L7, Canada; (M.S.A.); (H.T.); (R.G.-A.); (D.-Y.W.)
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
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7
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Desai K, Wanggou S, Luis E, Whetstone H, Yu C, Vanner RJ, Selvadurai HJ, Lee L, Vijay J, Jaramillo JE, Fan J, Guilhamon P, Kushida M, Li X, Stein G, Kesari S, Simons BD, Huang X, Dirks PB. OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma. Nat Commun 2025; 16:1092. [PMID: 39904987 PMCID: PMC11794873 DOI: 10.1038/s41467-024-54858-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/22/2024] [Indexed: 02/06/2025] Open
Abstract
Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy.
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Affiliation(s)
- Kinjal Desai
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Siyi Wanggou
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- Department of Neurosurgery, and Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Erika Luis
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Heather Whetstone
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Chunying Yu
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Robert J Vanner
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Hayden J Selvadurai
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Lilian Lee
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Jinchu Vijay
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Julia E Jaramillo
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Jerry Fan
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Paul Guilhamon
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Michelle Kushida
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Xuejun Li
- Department of Neurosurgery, and Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Gregory Stein
- Curtana Pharmaceuticals, Inc, Austin, TX, 78756, USA
| | - Santosh Kesari
- Curtana Pharmaceuticals, Inc, Austin, TX, 78756, USA
- Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA
| | - Benjamin D Simons
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, CB3 0WA, UK
- The Wellcome Trust/Cancer Research UK Gurdon Institute, and the Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QN, UK
| | - Xi Huang
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Peter B Dirks
- Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
- Division of Neurosurgery, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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8
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Van den Bossche V, Vignau J, Vigneron E, Rizzi I, Zaryouh H, Wouters A, Ambroise J, Van Laere S, Beyaert S, Helaers R, van Marcke C, Mignion L, Lepicard EY, Jordan BF, Guilbaud C, Lowyck O, Dahou H, Mendola A, Desgres M, Aubert L, Gerin I, Bommer GT, Boidot R, Vermonden P, Warnant A, Larondelle Y, Machiels JP, Feron O, Schmitz S, Corbet C. PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma. Nat Commun 2025; 16:1237. [PMID: 39890801 PMCID: PMC11785796 DOI: 10.1038/s41467-025-56675-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/24/2025] [Indexed: 02/03/2025] Open
Abstract
Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy.
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Affiliation(s)
- Valentin Van den Bossche
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
| | - Julie Vignau
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
| | - Engy Vigneron
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
| | - Isabella Rizzi
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
| | - Hannah Zaryouh
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
| | - An Wouters
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium
| | - Jérôme Ambroise
- Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 54, B-1200, Brussels, Belgium
| | - Steven Van Laere
- Translational Cancer Research Unit (TCRU), GZA Ziekenhuizen, Antwerp, Belgium
| | - Simon Beyaert
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
- Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
| | - Raphaël Helaers
- Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, B-1200, Brussels, Belgium
| | - Cédric van Marcke
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
| | - Lionel Mignion
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, B-1200, Brussels, Belgium
| | - Elise Y Lepicard
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, B-1200, Brussels, Belgium
| | - Bénédicte F Jordan
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, B-1200, Brussels, Belgium
| | - Céline Guilbaud
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
| | - Olivier Lowyck
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
| | - Hajar Dahou
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
| | - Antonella Mendola
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
| | - Manon Desgres
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
| | - Léo Aubert
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
| | - Isabelle Gerin
- Metabolic Research Group, de Duve Institute, UCLouvain, B-1200, Brussels, Belgium
| | - Guido T Bommer
- Metabolic Research Group, de Duve Institute, UCLouvain, B-1200, Brussels, Belgium
| | - Romain Boidot
- Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges‑François Leclerc Cancer Center‑UNICANCER, 21079, Dijon, France
- ICMUB UMR CNRS 6302, 21079, Dijon, France
| | - Perrine Vermonden
- Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Croix du Sud 4-5/L7.07.03, B-1348, Louvain-la-Neuve, Belgium
| | - Aurélien Warnant
- Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Croix du Sud 4-5/L7.07.03, B-1348, Louvain-la-Neuve, Belgium
| | - Yvan Larondelle
- Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Croix du Sud 4-5/L7.07.03, B-1348, Louvain-la-Neuve, Belgium
| | - Jean-Pascal Machiels
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
- Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
| | - Olivier Feron
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
- WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium
| | - Sandra Schmitz
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium
- Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium
| | - Cyril Corbet
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium.
- WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium.
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9
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Barateiro LGRP, de Oliveira Cavagna R, dos Reis MB, de Paula FE, Teixeira GR, Moreno DA, Bonatelli M, Santana I, Saggioro FP, Neder L, Stavale JN, Malheiros SMF, Garcia‐Rivello H, Christiansen S, Nunes S, da Costa MJG, Pinheiro J, Júnior CA, Mançano BM, Reis RM. Somatic mutational profiling and clinical impact of driver genes in Latin-Iberian medulloblastomas: Towards precision medicine. Neuropathology 2025; 45:30-37. [PMID: 38736183 PMCID: PMC11788001 DOI: 10.1111/neup.12979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/16/2024] [Accepted: 04/18/2024] [Indexed: 05/14/2024]
Abstract
Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, known for its heterogeneity and treatment-associated toxicity, and there is a critical need for new therapeutic targets. We analyzed the somatic mutation profile of 15 driver genes in 69 Latin-Iberian molecularly characterized medulloblastomas using the Illumina TruSight Tumor 15 panel. We classified the variants based on their clinical impact and oncogenicity. Among the patients, 66.7% were MBSHH, 13.0% MBWNT, 7.3% MBGrp3, and 13.0% MBGrp4. Among the 63 variants found, 54% were classified as Tier I/II and 31.7% as oncogenic/likely oncogenic. We observed 33.3% of cases harboring at least one mutation. TP53 (23.2%, 16/69) was the most mutated gene, followed by PIK3CA (5.8%, 4/69), KIT (4.3%, 3/69), PDGFRA (2.9%, 2/69), EGFR (1.4%, 1/69), ERBB2 (1.4%, 1/69), and NRAS (1.4%, 1/69). Approximately 41% of MBSHH tumors exhibited mutations, TP53 (32.6%) being the most frequently mutated gene. Tier I/II and oncogenic/likely oncogenic TP53 variants were associated with relapse, progression, and lower survival rates. Potentially actionable variants in the PIK3CA and KIT genes were identified. Latin-Iberian medulloblastomas, particularly the MBSHH, exhibit higher mutation frequencies than other populations. We corroborate the TP53 mutation status as an important prognostic factor, while PIK3CA and KIT are potential therapeutic targets.
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Affiliation(s)
| | | | | | | | - Gustavo Ramos Teixeira
- Molecular Diagnostic LaboratoryBarretos Cancer HospitalBarretosBrazil
- Department of PathologyBarretos Cancer HospitalBarretosBrazil
| | | | - Murilo Bonatelli
- Molecular Diagnostic LaboratoryBarretos Cancer HospitalBarretosBrazil
| | - Iara Santana
- Department of PathologyBarretos Cancer HospitalBarretosBrazil
| | | | - Luciano Neder
- Ribeirão Preto Medical SchoolUniversity of São PauloSão PauloBrazil
| | | | | | | | | | | | | | | | | | | | - Rui Manuel Reis
- Molecular Oncology Research CenterBarretos Cancer HospitalBarretosBrazil
- Molecular Diagnostic LaboratoryBarretos Cancer HospitalBarretosBrazil
- Life and Health Sciences Research Institute (ICVS), Medical SchoolUniversity of MinhoBragaPortugal
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10
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Fan JJ, Erickson AW, Carrillo-Garcia J, Wang X, Skowron P, Wang X, Chen X, Shan G, Dou W, Bahrampour S, Xiong Y, Dong W, Abeysundara N, Francisco MA, Pusong RJ, Wang W, Li M, Ying E, Suárez RA, Farooq H, Holgado BL, Wu X, Daniels C, Dupuy AJ, Cadiñanos J, Bradley A, Bagchi A, Moriarity BS, Largaespada DA, Morrissy AS, Ramaswamy V, Mack SC, Garzia L, Dirks PB, Li X, Wanggou S, Egan S, Sun Y, Taylor MD, Huang X. A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance. Dev Cell 2025:S1534-5807(25)00001-2. [PMID: 39862856 DOI: 10.1016/j.devcel.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/28/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025]
Abstract
Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells (MPCs), with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of epidermal growth factor receptor (EGFR), thereby mitigating proliferation of MPCs to ultimately impair MB growth. KCNB2 is largely dispensable for mouse development and KCNB2 knockout synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance drivers and elucidate a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote MB aggression.
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Affiliation(s)
- Jerry J Fan
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Anders W Erickson
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Julia Carrillo-Garcia
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Xin Wang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Patryk Skowron
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Xian Wang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Xin Chen
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Guanqiao Shan
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Wenkun Dou
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Shahrzad Bahrampour
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Yi Xiong
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Weifan Dong
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Namal Abeysundara
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Michelle A Francisco
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Ronwell J Pusong
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Wei Wang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Miranda Li
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Elliot Ying
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Raúl A Suárez
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Hamza Farooq
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Borja L Holgado
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Xiaochong Wu
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Craig Daniels
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Adam J Dupuy
- Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA
| | - Juan Cadiñanos
- Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo 33193, Spain
| | - Allan Bradley
- T-Therapeutics Ltd. One Riverside, Granta Park, Cambridge CB21 6AD, UK
| | - Anindya Bagchi
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Branden S Moriarity
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - David A Largaespada
- Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - A Sorana Morrissy
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2T8, Canada
| | - Vijay Ramaswamy
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
| | - Stephen C Mack
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Developmental Neurobiology, Neurobiology and Brain Tumor Program, Center of Excellence in Neuro-Oncology Sciences, St Jude Children's Hospital, Memphis, TN 38105, USA
| | - Livia Garzia
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal, QC H4A 3J1, Canada; Cancer Research Program, RI-MUHC, Montreal, QC H4A 3J1, Canada
| | - Peter B Dirks
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Siyi Wanggou
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Sean Egan
- Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Yu Sun
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Michael D Taylor
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Xi Huang
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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11
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Beh CY, Yeo CPX, Hong BH, Tan EMC, Tan KM, Poon DJJ, Chu PL, Susanti D, Tai PL, Ryu M, Proudfoot J, Yeo ELL, Soo KC, Chua MLK. Genomic and transcriptomic profiling of radioresistant prostate and head and neck cancers implicate a BAHD1-dependent modification of DNA damage at the heterochromatin. Cell Death Dis 2024; 15:929. [PMID: 39719436 DOI: 10.1038/s41419-024-07316-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/01/2024] [Accepted: 12/17/2024] [Indexed: 12/26/2024]
Abstract
Radiotherapy is an integral modality in treating human cancers, but radioresistance remains a clinical challenge due to the involvement of multiple intrinsic cellular and extrinsic tumour microenvironment factors that govern radiosensitivity. To study the intrinsic factors that are associated with cancer radioresistance, we established 4 radioresistant prostate (22Rv1 and DU145) and head and neck cancer (FaDu and HK1) models by irradiating their wild-type parentals to 90 Gy, mimicking the fractionated radiotherapy schema that is often using in the clinic, and performed whole exome and transcriptome sequencing of the radioresistant and wild-type models. Comparative genomic analyses detected the enrichment of mismatch repair mutational signatures (SBS6, 14, 15, 20) across all the cell lines and several non-synonymous single nucleotide variants involved in pro-survival pathways. Despite significant inter-cell type heterogeneity of their transcriptomic profiles, 18 common dysregulated genes (5 upregulated and 13 downregulated) were identified across the 4 models, including the overexpression of bromo-adjacent homology domain containing 1 (BAHD1) gene, which is involved in heterochromatin formation. Interestingly, this coincided with our observation of increased histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) expression post-irradiation in our radioresistant cells. The dependency between BAHD1 and heterochromatin formation was confirmed by siRNA knockdown of BAHD1, indicating preferential reduction of H3K9me3 and H3K27me3 expression in the radioresistant cells, but not the wild-type parentals, and confirmed by clonogenic assays showing reversal of radioresistance post-siBAHD1 treatment. We further showed that inhibition of the BAHD1-heterochromatin formation axis led to reduced DNA double-strand break repair. Finally, analyses of treatment outcomes in 4 prostate and head and neck cancer radiotherapy cohorts suggested an increased risk of failures in tumours of high heterochromatin activity. Taken together, our results support a new model implicating BAHD1-dependent modulation of the heterochromatin in acquired radioresistance of prostate and head and neck cancers.
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Affiliation(s)
- Chaw Yee Beh
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Celestia Pei Xuan Yeo
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Boon Hao Hong
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Evelyn Mui Cheng Tan
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Kah Min Tan
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Dennis Jun Jie Poon
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Pek Lim Chu
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Dewi Susanti
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Pei Ling Tai
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | | | | | - Eugenia Li Ling Yeo
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Khee Chee Soo
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore
| | - Melvin L K Chua
- Division of Medical Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, 168583, Singapore, Singapore.
- Division of Radiation Oncology, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Singapore.
- Oncology Academic Programme, Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore.
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12
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Rhinehart DP, Lai J, Sanin DE, Vakkala V, Mendes A, Bailey C, Antonarakis ES, Paller CJ, Wu X, Lotan TL, Karchin R, Sena LA. Intratumoral heterogeneity drives acquired therapy resistance in a patient with metastatic prostate cancer. NPJ Precis Oncol 2024; 8:275. [PMID: 39623053 PMCID: PMC11612198 DOI: 10.1038/s41698-024-00773-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024] Open
Abstract
Metastatic prostate cancer (PCa) is not curable due to its ability to acquire therapy resistance. Theoretically, acquired therapy resistance can be driven by changes to previously sensitive cancer cells or their environment and/or by outgrowth of a subpopulation of cancer cells with primary resistance. Direct demonstration of the latter mechanism in patients with PCa is lacking. Here we present a case report as proof-of-principle that outgrowth of a subpopulation of cancer cells lacking the genomic target and present prior to therapy initiation can drive acquired resistance to targeted therapy and threaten survival in patients with PCa.
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Affiliation(s)
- Dena P Rhinehart
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Jiaying Lai
- Institute for Computational Medicine at Johns Hopkins University, Baltimore, MD, USA
| | - David E Sanin
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Varsha Vakkala
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Adrianna Mendes
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Christopher Bailey
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | | | - Channing J Paller
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Xiaojun Wu
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Tamara L Lotan
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Rachel Karchin
- Institute for Computational Medicine at Johns Hopkins University, Baltimore, MD, USA.
| | - Laura A Sena
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
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13
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Kats I, Simovic-Lorenz M, Schreiber HS, Sant P, Mallm JP, Körber V, Li A, Velmurugan P, Heuer S, Kües L, Devens F, Sill M, Jugold M, Moustafa M, Abdollahi A, Winkler F, Korshunov A, Pfister SM, Stegle O, Ernst A. Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse. Nat Commun 2024; 15:10370. [PMID: 39609432 PMCID: PMC11604656 DOI: 10.1038/s41467-024-54709-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 11/18/2024] [Indexed: 11/30/2024] Open
Abstract
Paediatric medulloblastomas with chromothripsis are characterised by high genomic instability and are among the tumours with the worst prognosis. However, the molecular makeup and the determinants of the aggressiveness of chromothriptic medulloblastoma are not well understood. Here, we apply spatial transcriptomics to profile a cohort of 13 chromothriptic and non-chromothriptic medulloblastomas from the same molecular subgroup. Our data reveal a higher extent of spatial intra-tumour heterogeneity in chromothriptic medulloblastomas compared to non-chromothripictic tumours, which is associated with increased proliferation and stemness, but lower immune infiltration and differentiation. Spatial mapping of genetic subclones of the same tumour identify a regionally distinct architecture and clone-specific phenotypic features, with distinct degrees of differentiation, proliferation and immune infiltration between clones. We conduct temporal profiling of 11 samples from patient-derived xenografts from a patient with chromothriptic medulloblastoma, covering the transition from the minimal residual disease stage to treatment-resistant regrown tumours. In chromothriptic medulloblastoma, an ecosystem of cells from multiple genetic clones resist treatment and lead to relapse. Finally, we identify tumour microtubes in chromothriptic medulloblastoma, calling for exploration of cell network communication as a putative target.
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Affiliation(s)
- Ilia Kats
- Division of Computational Genomics and Systems Genetics, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Milena Simovic-Lorenz
- Group Genome Instability in Tumors, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Hannah Sophia Schreiber
- Group Genome Instability in Tumors, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Pooja Sant
- Single Cell Open Lab, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan-Philipp Mallm
- Single Cell Open Lab, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Verena Körber
- MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Albert Li
- Group Genome Instability in Tumors, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Pravin Velmurugan
- Group Genome Instability in Tumors, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Sophie Heuer
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Neurological Clinic, Heidelberg University Hospital (UKHD), Heidelberg, Germany
- Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Luisa Kües
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Neurological Clinic, Heidelberg University Hospital (UKHD), Heidelberg, Germany
- Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Frauke Devens
- Group Genome Instability in Tumors, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Martin Sill
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Manfred Jugold
- Core Facility Small Animal Imaging Center, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mahmoud Moustafa
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany
- Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt
| | - Amir Abdollahi
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany
| | - Frank Winkler
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Neurological Clinic, Heidelberg University Hospital (UKHD), Heidelberg, Germany
- Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Andrey Korshunov
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Hospital (UKHD), Heidelberg, Germany
| | - Stefan M Pfister
- German Cancer Consortium (DKTK), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital (UKHD), Heidelberg, Germany
| | - Oliver Stegle
- Division of Computational Genomics and Systems Genetics, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
| | - Aurélie Ernst
- Group Genome Instability in Tumors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
- German Cancer Consortium (DKTK), Heidelberg, Germany.
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14
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Abstract
The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.
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Affiliation(s)
- Lucie Laplane
- UMR 8590 Institut d'Histoire et Philosophie des Sciences et des Techniques, CNRS, University Paris I Pantheon-Sorbonne, Paris, France
- UMR 1287 Hematopoietic Tissue Aging, Gustave Roussy Cancer Campus, Villejuif, France
| | - Carlo C Maley
- Arizona Cancer Evolution Center, Arizona State University, Tempe, AZ, USA.
- School of Life Sciences, Arizona State University, Tempe, AZ, USA.
- Biodesign Center for Biocomputing, Security and Society, Arizona State University, Tempe, AZ, USA.
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.
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15
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Peterson K, Turos-Cabal M, Salvador AD, Palomo-Caturla I, Howell AJ, Vieira ME, Greiner SM, Barnoud T, Rodriguez-Blanco J. Mechanistic insights into medulloblastoma relapse. Pharmacol Ther 2024; 260:108673. [PMID: 38857789 PMCID: PMC11270902 DOI: 10.1016/j.pharmthera.2024.108673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.
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Affiliation(s)
- Kendell Peterson
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Maria Turos-Cabal
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - April D Salvador
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | | | - Ashley J Howell
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Megan E Vieira
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Sean M Greiner
- Department of Pediatrics, Johns Hopkins Children's Center, Baltimore, MD, USA
| | - Thibaut Barnoud
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Jezabel Rodriguez-Blanco
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
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16
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Zeng X, Chen Q, Chen T. Nanomaterial-assisted oncolytic bacteria in solid tumor diagnosis and therapeutics. Bioeng Transl Med 2024; 9:e10672. [PMID: 39036084 PMCID: PMC11256190 DOI: 10.1002/btm2.10672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/29/2024] [Accepted: 04/08/2024] [Indexed: 07/23/2024] Open
Abstract
Cancer presents a formidable challenge in modern medicine due to the intratumoral heterogeneity and the dynamic microenvironmental niche. Natural or genetically engineered oncolytic bacteria have always been hailed by scientists for their intrinsic tumor-targeting and oncolytic capacities. However, the immunogenicity and low toxicity inevitably constrain their application in clinical practice. When nanomaterials, characterized by distinctive physicochemical properties, are integrated with oncolytic bacteria, they achieve mutually complementary advantages and construct efficient and safe nanobiohybrids. In this review, we initially analyze the merits and drawbacks of conventional tumor therapeutic approaches, followed by a detailed examination of the precise oncolysis mechanisms employed by oncolytic bacteria. Subsequently, we focus on harnessing nanomaterial-assisted oncolytic bacteria (NAOB) to augment the effectiveness of tumor therapy and utilizing them as nanotheranostic agents for imaging-guided tumor treatment. Finally, by summarizing and analyzing the current deficiencies of NAOB, this review provides some innovative directions for developing nanobiohybrids, intending to infuse novel research concepts into the realm of solid tumor therapy.
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Affiliation(s)
- Xiangdi Zeng
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
- The First Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Qi Chen
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Tingtao Chen
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
- National Engineering Research Center for Bioengineering Drugs and the TechnologiesInstitute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
- School of PharmacyJiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
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17
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Slika H, Shahani A, Wahi R, Miller J, Groves M, Tyler B. Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies. Cancers (Basel) 2024; 16:2249. [PMID: 38927954 PMCID: PMC11202166 DOI: 10.3390/cancers16122249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma's response to therapeutic modalities.
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Affiliation(s)
- Hasan Slika
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
| | - Aanya Shahani
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
| | - Riddhpreet Wahi
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
- Grant Government Medical College and Sir J.J Group of Hospitals, Mumbai 400008, India
| | - Jackson Miller
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
- Department of English, Rhetoric, and Humanistic Studies, Virginia Military Institute, Lexington, VA 24450, USA
| | - Mari Groves
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
- Department of Neurosurgery, University of Maryland Medical Center, Baltimore, MD 21201, USA
| | - Betty Tyler
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
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18
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Buckley DN, Tew BY, Gooden C, Salhia B. A comprehensive analysis of minimally differentially methylated regions common to pediatric and adult solid tumors. NPJ Precis Oncol 2024; 8:125. [PMID: 38824198 PMCID: PMC11144230 DOI: 10.1038/s41698-024-00590-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/14/2024] [Indexed: 06/03/2024] Open
Abstract
Cancer is the second most common cause of death in children aged 1-14 years in the United States, with 11,000 new cases and 1200 deaths annually. Pediatric cancers typically have lower mutational burden compared to adult-onset cancers, however, the epigenomes in pediatric cancer are highly altered, with widespread DNA methylation changes. The rarity of pediatric cancers poses a significant challenge to developing cancer-type specific biomarkers for diagnosis, prognosis, or treatment monitoring. In the current study, we explored the potential of a DNA methylation profile common across various pediatric cancers. To do this, we conducted whole genome bisulfite sequencing (WGBS) on 31 recurrent pediatric tumor tissues, 13 normal tissues, and 20 plasma cell-free (cf)DNA samples, representing 11 different pediatric cancer types. We defined minimal focal regions that were differentially methylated across samples in the multiple cancer types which we termed minimally differentially methylated regions (mDMRs). These methylation changes were also observed in 506 pediatric and 5691 adult cancer samples accessed from publicly available databases, and in 44 pediatric cancer samples we analyzed using a targeted hybridization probe capture assay. Finally, we found that these methylation changes were detectable in cfDNA and could serve as potential cfDNA methylation biomarkers for early detection or minimal residual disease.
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Affiliation(s)
- David N Buckley
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ben Yi Tew
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Chris Gooden
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Bodour Salhia
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
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19
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Do AD, Wu KS, Chu SS, Giang LH, Lin YL, Chang CC, Wong TT, Hsieh CL, Sung SY. LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes. J Exp Clin Cancer Res 2024; 43:130. [PMID: 38689348 PMCID: PMC11059759 DOI: 10.1186/s13046-024-03057-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 04/22/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Medulloblastomas (MBs) are one of the most common malignant brain tumor types in children. MB prognosis, despite improvement in recent years, still depends on clinical and biological risk factors. Metastasis is the leading cause of MB-related deaths, which highlights an unmet need for risk stratification and targeted therapy to improve clinical outcomes. Among the four molecular subgroups, sonic-hedgehog (SHH)-MB harbors clinical and genetic heterogeneity with a subset of high-risk cases. Recently, long non-coding (lnc)RNAs were implied to contribute to cancer malignant progression, but their role in MB remains unclear. This study aimed to identify pro-malignant lncRNAs that have prognostic and therapeutic significance in SHH-MB. METHODS The Daoy SHH-MB cell line was engineered for ectopic expression of MYCN, a genetic signature of SHH-MB. MYCN-associated lncRNA genes were identified using RNA-sequencing data and were validated in SHH-MB cell lines, MB tissue samples, and patient cohort datasets. SHH-MB cells with genetic manipulation of the candidate lncRNA were evaluated for metastatic phenotypes in vitro, including cell migration, invasion, sphere formation, and expressions of stemness markers. An orthotopic xenograft mouse model was used to evaluate metastasis occurrence and survival. Finally, bioinformatic screening and in vitro assays were performed to explore downstream mechanisms. RESULTS Elevated lncRNA LOXL1-AS1 expression was identified in MYCN-expressing Daoy cells and MYCN-amplified SHH-MB tumors, and was significantly associated with lower survival in SHH-MB patients. Functionally, LOXL1-AS1 promoted SHH-MB cell migration and cancer stemness in vitro. In mice, MYCN-expressing Daoy cells exhibited a high metastatic rate and adverse effects on survival, both of which were suppressed under LOLX1-AS1 perturbation. Integrative bioinformatic analyses revealed associations of LOXL1-AS1 with processes of cancer stemness, cell differentiation, and the epithelial-mesenchymal transition. LOXL1-AS1 positively regulated the expression of transforming growth factor (TGF)-β2. Knockdown of TGF-β2 in SHH-MB cells significantly abrogated their LOXL1-AS1-mediated prometastatic functions. CONCLUSIONS This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-β2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.
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Affiliation(s)
- Anh Duy Do
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, 700000, Vietnam
| | - Kuo-Sheng Wu
- Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Shing-Shung Chu
- Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Le Hien Giang
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- Department of Biology and Genetics, Hai Phong University of Medicine and Pharmacy, Hai Phong, 180000, Vietnam
| | - Yu-Ling Lin
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Che-Chang Chang
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan
| | - Tai-Tong Wong
- Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan
- Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Neuroscience Institute, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan
| | - Chia-Ling Hsieh
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan.
- Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, 11571, Taiwan.
| | - Shian-Ying Sung
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
- Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan.
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
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20
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Qi L, Baxter P, Kogiso M, Zhang H, Braun FK, Lindsay H, Zhao S, Xiao S, Abdallah AS, Suarez M, Huang Z, Teo WY, Yu L, Zhao X, Liu Z, Huang Y, Su JM, Man TK, Lau CC, Perlaky L, Du Y, Li XN. Direct Implantation of Patient Brain Tumor Cells into Matching Locations in Mouse Brains for Patient-Derived Orthotopic Xenograft Model Development. Cancers (Basel) 2024; 16:1716. [PMID: 38730671 PMCID: PMC11083000 DOI: 10.3390/cancers16091716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/11/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.
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Affiliation(s)
- Lin Qi
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Sun Yat-sen University, Shenzhen 510080, China;
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
| | - Patricia Baxter
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mari Kogiso
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Huiyuan Zhang
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Frank K. Braun
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Holly Lindsay
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sibo Zhao
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sophie Xiao
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
| | - Aalaa Sanad Abdallah
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
| | - Milagros Suarez
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
| | - Zilu Huang
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
| | - Wan Yee Teo
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- The Laboratory of Pediatric Brain Tumor Research Office, SingHealth Duke-NUS Academic Medical Center, Singapore 169856, Singapore
| | - Litian Yu
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiumei Zhao
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhigang Liu
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yulun Huang
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jack M. Su
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
| | - Tsz-Kwong Man
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
| | - Ching C. Lau
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
| | - Laszlo Perlaky
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
| | - Yuchen Du
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA
| | - Xiao-Nan Li
- Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA; (P.B.); (M.K.); (H.Z.); (F.K.B.); (H.L.); (S.Z.); (W.Y.T.); (L.Y.); (X.Z.); (Z.L.); (Y.H.); (J.M.S.); (T.-K.M.); (C.C.L.); (L.P.)
- Laboratory of Molecular Neuro-Oncology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (S.X.); (A.S.A.); (M.S.); (Z.H.)
- The Laboratory of Pediatric Brain Tumor Research Office, SingHealth Duke-NUS Academic Medical Center, Singapore 169856, Singapore
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21
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Abstract
Pediatric precision oncology has provided a greater understanding of the wide range of molecular alterations in difficult-to-treat or rare tumors with the aims of increasing survival as well as decreasing toxicity and morbidity from current cytotoxic therapies. In this article, the authors discuss the current state of pediatric precision oncology which has increased access to novel targeted therapies while also providing a framework for clinical implementation in this unique population. The authors evaluate the targetable mutations currently under investigation-with a focus on pediatric solid tumors-and discuss the key surgical implications associated with novel targeted therapies.
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Affiliation(s)
- William G Lee
- Department of Surgery, Cedars-Sinai Medical Center, 116 North Robertson Boulevard, Suite PACT 700, Los Angeles, CA 90048, USA. https://twitter.com/william_ghh_lee
| | - Eugene S Kim
- Division of Pediatric Surgery, Department of Surgery, Cedars-Sinai Medical Center, 116 North Robertson Boulevard, Suite PACT 700, Los Angeles, CA 90048, USA.
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22
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Sheng H, Li H, Zeng H, Zhang B, Lu Y, Liu X, Xu Z, Zhang J, Zhang L. Heterogeneity and tumoral origin of medulloblastoma in the single-cell era. Oncogene 2024; 43:839-850. [PMID: 38355808 PMCID: PMC10942862 DOI: 10.1038/s41388-024-02967-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 02/05/2024] [Indexed: 02/16/2024]
Abstract
Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong the survival time with severe side effects and relapse. Defining the intratumoral heterogeneity, cellular origin and identifying the interaction network within tumor microenvironment are helpful for understanding the mechanisms of medulloblastoma tumorigenesis and relapse. Due to technological limitations, the mechanisms of cellular heterogeneity and tumor origin have not been fully understood. Recently, the emergence of single-cell technology has provided a powerful tool for achieving the goal of understanding the mechanisms of tumorigenesis. Several studies have demonstrated the intratumoral heterogeneity and tumor origin for each subtype of medulloblastoma utilizing the single-cell RNA-seq, which has not been uncovered before using conventional technologies. In this review, we present an overview of the current progress in understanding of cellular heterogeneity and tumor origin of medulloblastoma and discuss novel findings in the age of single-cell technologies.
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Affiliation(s)
- Hui Sheng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Haotai Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Han Zeng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yu Lu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xixi Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhongwen Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Zhang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liguo Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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23
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Han M, Perkins MH, Novaes LS, Xu T, Chang H. Advances in transposable elements: from mechanisms to applications in mammalian genomics. Front Genet 2023; 14:1290146. [PMID: 38098473 PMCID: PMC10719622 DOI: 10.3389/fgene.2023.1290146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/13/2023] [Indexed: 12/17/2023] Open
Abstract
It has been 70 years since Barbara McClintock discovered transposable elements (TE), and the mechanistic studies and functional applications of transposable elements have been at the forefront of life science research. As an essential part of the genome, TEs have been discovered in most species of prokaryotes and eukaryotes, and the relative proportion of the total genetic sequence they comprise gradually increases with the expansion of the genome. In humans, TEs account for about 40% of the genome and are deeply involved in gene regulation, chromosome structure maintenance, inflammatory response, and the etiology of genetic and non-genetic diseases. In-depth functional studies of TEs in mammalian cells and the human body have led to a greater understanding of these fundamental biological processes. At the same time, as a potent mutagen and efficient genome editing tool, TEs have been transformed into biological tools critical for developing new techniques. By controlling the random insertion of TEs into the genome to change the phenotype in cells and model organisms, critical proteins of many diseases have been systematically identified. Exploiting the TE's highly efficient in vitro insertion activity has driven the development of cutting-edge sequencing technologies. Recently, a new technology combining CRISPR with TEs was reported, which provides a novel targeted insertion system to both academia and industry. We suggest that interrogating biological processes that generally depend on the actions of TEs with TEs-derived genetic tools is a very efficient strategy. For example, excessive activation of TEs is an essential factor in the occurrence of cancer in humans. As potent mutagens, TEs have also been used to unravel the key regulatory elements and mechanisms of carcinogenesis. Through this review, we aim to effectively combine the traditional views of TEs with recent research progress, systematically link the mechanistic discoveries of TEs with the technological developments of TE-based tools, and provide a comprehensive approach and understanding for researchers in different fields.
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Affiliation(s)
- Mei Han
- Guangzhou National Laboratory, Guangzhou, China
| | - Matthew H. Perkins
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Leonardo Santana Novaes
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Tao Xu
- Guangzhou National Laboratory, Guangzhou, China
| | - Hao Chang
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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24
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Mariotto E, Rampazzo E, Bortolozzi R, Rruga F, Zeni I, Manfreda L, Marchioro C, Canton M, Cani A, Magni R, Luchini A, Bresolin S, Viola G, Persano L. Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma. Acta Neuropathol Commun 2023; 11:183. [PMID: 37978570 PMCID: PMC10655385 DOI: 10.1186/s40478-023-01679-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023] Open
Abstract
Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.
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Affiliation(s)
- Elena Mariotto
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
- Unit of Biostatistics, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Via Loredan 18, 35131, Padua, Italy
| | - Elena Rampazzo
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy.
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy.
| | - Roberta Bortolozzi
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy.
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy.
- Section of Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131, Padua, Italy.
| | - Fatlum Rruga
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Ilaria Zeni
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
| | - Lorenzo Manfreda
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Chiara Marchioro
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Martina Canton
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Alice Cani
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Ruben Magni
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, MSN 1A9, Manassas, VA, 20110, USA
| | - Alessandra Luchini
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, MSN 1A9, Manassas, VA, 20110, USA
| | - Silvia Bresolin
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Giampietro Viola
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Luca Persano
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
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25
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Gallo-Oller G, de Ståhl TD, Alaiya A, Nilsson S, Holmberg AR, Márquez-Méndez M. Cytotoxicity of poly-guanidine in medulloblastoma cell lines. Invest New Drugs 2023; 41:688-698. [PMID: 37556022 PMCID: PMC10560188 DOI: 10.1007/s10637-023-01386-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/14/2023] [Indexed: 08/10/2023]
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor. The therapy frequently causes serious side effects, and new selective therapies are needed. MB expresses hyper sialylation, a possible target for selective therapy. The cytotoxic efficacy of a poly guanidine conjugate (GuaDex) incubated with medulloblastoma cell cultures (DAOY and MB-LU-181) was investigated. The cells were incubated with 0.05-8 µM GuaDex from 15 min to 72 h. A fluorometric cytotoxicity assay (FMCA) measured the cytotoxicity. Labeled GuaDex was used to study tumor cell interaction. FITC-label Sambucus nigra confirmed high expression of sialic acid (Sia). Immunofluorescence microscopy was used to visualize the cell F-actin and microtubules. The cell interactions were studied by confocal and fluorescence microscopy. Annexin-V assay was used to detect apoptosis. Cell cycle analysis was done by DNA content determination. A wound-healing migration assay determined the effects on the migratory ability of DAOY cells after GuaDex treatment. IC50 for GuaDex was 223.4 -281.1 nM. FMCA showed potent growth inhibition on DAOY and MB-LU-181 cells at 5 uM GuaDex after 4 h of incubation. GuaDex treatment induced G2/M phase cell cycle arrest. S. nigra FITC-label lectin confirmed high expression of Sia on DAOY medulloblastoma cells. The GuaDex treatment polymerized the cytoskeleton (actin filaments and microtubules) and bound to DNA, inducing condensation. The Annexin V assay results were negative. Cell migration was inhibited at 0.5 µM GuaDex concentration after 24 h of incubation. GuaDex showed potent cytotoxicity and invasion-inhibitory effects on medulloblastoma cells at low micromolar concentrations. GuaDex efficacy was significant and warrants further studies.
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Affiliation(s)
- Gabriel Gallo-Oller
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | | | - Ayodele Alaiya
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Cell Therapy and Immunobiology Department, King Faisal Specialist Hospital and Research Centre Oncology Centre, Riyadh, Saudi Arabia
| | - Sten Nilsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Anders R Holmberg
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Marcela Márquez-Méndez
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- Center for Research and Development in Health Sciences, Autonomous University of Nuevo León, Monterrey, N.L., Mexico.
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26
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Koukourakis MI, Xanthopoulou E, Koukourakis IM, Fortis SP, Kesesidis N, Kakouratos C, Karakasiliotis I, Baxevanis CN. Next-Generation Sequencing Analysis of Mutations in Circulating Tumor DNA from the Plasma of Patients with Head-Neck Cancer Undergoing Chemo-Radiotherapy Using a Pan-Cancer Cell-Free Assay. Curr Oncol 2023; 30:8902-8915. [PMID: 37887543 PMCID: PMC10604986 DOI: 10.3390/curroncol30100643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/18/2023] [Accepted: 09/27/2023] [Indexed: 10/28/2023] Open
Abstract
Using next-generation sequencing (NGS), we investigated DNA mutations in the plasma tumor cell-free circulating DNA (ctDNA) of 38 patients with inoperable squamous cell head neck cancer (SCHNC) before and after the completion of chemoradiotherapy (CRT). Baseline mutations of the TP53 were recorded in 10/38 (26.3%) and persisted in 4/10 patients after CRT. ΤP53 mutations were further detected post CRT in 7/38 additional patients with undetectable mutations at baseline (overall rate 44.7%). Furthermore, 4/38 patients exhibited baseline mutations of the EGFR, AR, FGFR3, and FBXW3, and four new gene mutations were detected after CRT (MTOR, EGFR3, ALK, and SF3B1). Τ4 stage was related with a significantly higher rate of mutations (TP53 and overall). Mutations were observed in 8/30 (26.6%) responders (complete/partial response) vs. in 6/8 (75%) of the rest of the patients (p = 0.03). Significant poorer LRFS was noted for patients with mutations detected before and after CRT (p = 0.02). Patients who had detectable mutations either before or after CRT had significantly worse DMFS (p = 0.04 overall, and p = 0.02 for TP53 mutations). It was concluded that assessment of mutations before and after the end of CRT is essential to characterize patients with a high risk of locoregional recurrence or metastatic progression.
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Affiliation(s)
- Michael I. Koukourakis
- Department of Radiotherapy—Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (C.K.)
| | - Erasmia Xanthopoulou
- Department of Radiotherapy—Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (C.K.)
| | - Ioannis M. Koukourakis
- Radiation Oncology Unit, 1st Department of Radiology, Aretaieion University Hospital, 11528 Athens, Greece;
| | - Sotirios P. Fortis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece; (S.P.F.); (C.N.B.)
| | - Nikolaos Kesesidis
- Laboratory of Biology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.K.); (I.K.)
| | - Christos Kakouratos
- Department of Radiotherapy—Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.X.); (C.K.)
| | - Ioannis Karakasiliotis
- Laboratory of Biology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.K.); (I.K.)
| | - Constantin N. Baxevanis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece; (S.P.F.); (C.N.B.)
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27
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Moreno DA, Bonatelli M, Antoniazzi AP, de Paula FE, Leal LF, Garcia FADO, de Paula AE, Teixeira GR, Santana IVV, Saggioro F, Neder L, Valera ET, Scrideli CA, Stavale J, Malheiros SMF, Lima M, Hajj GNM, Garcia-Rivello H, Christiansen S, Nunes S, Gil-da-Costa MJ, Pinheiro J, Martins FD, Junior CA, Mançano BM, Reis RM. High frequency of WNT-activated medulloblastomas with CTNNB1 wild type suggests a higher proportion of hereditary cases in a Latin-Iberian population. Front Oncol 2023; 13:1237170. [PMID: 37746264 PMCID: PMC10513896 DOI: 10.3389/fonc.2023.1237170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/31/2023] [Indexed: 09/26/2023] Open
Abstract
Purpose Medulloblastomas are the most common primary malignant brain tumors in children. They are divided into molecular subgroups: WNT-activated, SHH-Activated, TP53 mutant or wild type, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated medulloblastomas are usually caused by mutations in the CTNNB1 gene (85%-90%), and most remaining cases of CTNNB1 wild type are thought to be caused by germline mutations in APC. So far, the frequencies of CTNNB1 have been reported mainly in North American and European populations. The aim of this study was to report the frequency of CTNNB1 mutations in WNT-activated medulloblastomas in a Latin-Iberian population and correlate with their clinicopathological characteristics. Methods A total of 266 medulloblastomas from seven different institutions from Brazil (n=211), Portugal (n=38), and Argentina (n=17) were evaluated. Following RNA and DNA isolation from formalin-fixed, paraffin-embedded (FFPE) tumor tissues, the molecular classification and CTNNB1 mutation analysis were performed by nCounter and Sanger sequencing, respectively. Results WNT-activated medulloblastomas accounted for 15% (40/266) of the series. We observed that 73% of WNT-activated medulloblastomas harbored CTNNB1 mutations. CTNNB1 wild-type cases (27%) were more prevalent in female individuals and suggested to be associated with a worse outcome. Among the CTNNB1 wild-type cases, the available analysis of family history revealed two cases with familiar adenomatous polyposis, harboring APC germline variants. Conclusion We observed a lower incidence of CTNNB1 mutations in WNT-activated medulloblastomas in our Latin-Iberian cohort compared to frequencies previously described in other populations. Considering that CTNNB1 wild-type cases may exhibit APC germline mutations, our study suggests a higher incidence (~30%) of hereditary WNT-activated medulloblastomas in the Latin-Iberian population.
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Affiliation(s)
| | - Murilo Bonatelli
- Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, Brazil
| | | | | | - Leticia Ferro Leal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
- Pathology Department, Barretos Cancer Hospital, Barretos, Brazil
| | | | | | - Gustavo Ramos Teixeira
- Barretos School of Health Sciences Dr. Paulo Prata, Barretos Cancer Hospital, Barretos, Brazil
- Pathology Department, Barretos Cancer Hospital, Barretos, Brazil
| | | | - Fabiano Saggioro
- Department of Pathology and Forensic Medicine, University of São Paulo, Ribeirão Preto, Brazil
| | - Luciano Neder
- Department of Pathology and Forensic Medicine, University of São Paulo, Ribeirão Preto, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Carlos Alberto Scrideli
- Department of Pediatrics of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - João Stavale
- Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | | | - Matheus Lima
- Oncology Department, AC Camargo Hospital, São Paulo, Brazil
| | | | | | - Silvia Christiansen
- Pathology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Susana Nunes
- Pediatric Oncology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | | | - Jorge Pinheiro
- Department of Pathology, Centro Hospitalar Universitário São João, Porto, Portugal
| | | | | | | | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
- Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, Brazil
- ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
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28
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Reuss DE, Downing SM, Camacho CV, Wang YD, Piro RM, Herold-Mende C, Wang ZQ, Hofmann TG, Sahm F, von Deimling A, McKinnon PJ, Frappart PO. Simultaneous Nbs1 and p53 inactivation in neural progenitors triggers high-grade gliomas. Neuropathol Appl Neurobiol 2023; 49:e12915. [PMID: 37296499 DOI: 10.1111/nan.12915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 04/25/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023]
Abstract
AIMS Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by hypomorphic mutations of NBS1. NBS1 is a member of the MRE11-RAD50-NBS1 (MRN) complex that binds to DNA double-strand breaks and activates the DNA damage response (DDR). Nbs1 inactivation in neural progenitor cells leads to microcephaly and premature death. Interestingly, p53 homozygous deletion rescues the NBS1-deficient phenotype allowing long-term survival. The objective of this work was to determine whether simultaneous inactivation of Nbs1 and p53 in neural progenitors triggered brain tumorigenesis and if so in which category this tumour could be classified. METHODS We generated a mouse model with simultaneous genetic inactivation of Nbs1 and p53 in embryonic neural stem cells and analysed the arising tumours with in-depth molecular analyses including immunohistochemistry, array comparative genomic hybridisation (aCGH), whole exome-sequencing and RNA-sequencing. RESULTS NBS1/P53-deficient mice develop high-grade gliomas (HGG) arising in the olfactory bulbs and in the cortex along the rostral migratory stream. In-depth molecular analyses using immunohistochemistry, aCGH, whole exome-sequencing and RNA-sequencing revealed striking similarities to paediatric human HGG with shared features with radiation-induced gliomas (RIGs). CONCLUSIONS Our findings show that concomitant inactivation of Nbs1 and p53 in mice promotes HGG with RIG features. This model could be useful for preclinical studies to improve the prognosis of these deadly tumours, but it also highlights the singularity of NBS1 among the other DNA damage response proteins in the aetiology of brain tumours.
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Affiliation(s)
- David E Reuss
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
| | - Susanna M Downing
- Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Cristel V Camacho
- Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Yong-Dong Wang
- Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Rosario M Piro
- Dipartimento di Elettronica, Informazione e Bioingegneria (DEIB), Politecnico di Milano, Milan, Italy
| | - Christel Herold-Mende
- Department of Neurosurgery, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
| | - Zhao-Qi Wang
- Leibniz Institute on Ageing-Fritz Lipmann Institute, Jena, Germany
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Thomas G Hofmann
- Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Felix Sahm
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
| | - Andreas von Deimling
- Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
| | - Peter J McKinnon
- Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Pierre-Olivier Frappart
- Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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29
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Netterfield TS, Ostheimer GJ, Tentner AR, Joughin BA, Dakoyannis AM, Sharma CD, Sorger PK, Janes KA, Lauffenburger DA, Yaffe MB. Biphasic JNK-Erk signaling separates the induction and maintenance of cell senescence after DNA damage induced by topoisomerase II inhibition. Cell Syst 2023; 14:582-604.e10. [PMID: 37473730 PMCID: PMC10627503 DOI: 10.1016/j.cels.2023.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 03/24/2023] [Accepted: 06/13/2023] [Indexed: 07/22/2023]
Abstract
Genotoxic stress in mammalian cells, including those caused by anti-cancer chemotherapy, can induce temporary cell-cycle arrest, DNA damage-induced senescence (DDIS), or apoptotic cell death. Despite obvious clinical importance, it is unclear how the signals emerging from DNA damage are integrated together with other cellular signaling pathways monitoring the cell's environment and/or internal state to control different cell fates. Using single-cell-based signaling measurements combined with tensor partial least square regression (t-PLSR)/principal component analysis (PCA) analysis, we show that JNK and Erk MAPK signaling regulates the initiation of cell senescence through the transcription factor AP-1 at early times after doxorubicin-induced DNA damage and the senescence-associated secretory phenotype (SASP) at late times after damage. These results identify temporally distinct roles for signaling pathways beyond the classic DNA damage response (DDR) that control the cell senescence decision and modulate the tumor microenvironment and reveal fundamental similarities between signaling pathways responsible for oncogene-induced senescence (OIS) and senescence caused by topoisomerase II inhibition. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Tatiana S Netterfield
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Gerard J Ostheimer
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Andrea R Tentner
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Brian A Joughin
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Alexandra M Dakoyannis
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Charvi D Sharma
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Computer Science and Molecular Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Peter K Sorger
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Kevin A Janes
- Department of Biomedical Engineering and Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Michael B Yaffe
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Acute Care Surgery, Trauma, and Surgical Critical Care, and Division of Surgical Oncology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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30
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Rechberger JS, Toll SA, Vanbilloen WJF, Daniels DJ, Khatua S. Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment. Diagnostics (Basel) 2023; 13:2398. [PMID: 37510143 PMCID: PMC10378552 DOI: 10.3390/diagnostics13142398] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.
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Affiliation(s)
- Julian S Rechberger
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Stephanie A Toll
- Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI 48201, USA
| | - Wouter J F Vanbilloen
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Neurology, Elisabeth-Tweesteden Hospital, 5022 Tilburg, The Netherlands
| | - David J Daniels
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Soumen Khatua
- Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN 55905, USA
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31
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Adile AA, Bakhshinyan D, Suk Y, Uehling D, Saini M, Aman A, Magolan J, Subapanditha MK, McKenna D, Chokshi C, Savage N, Kameda-Smith MM, Venugopal C, Singh SK. An effective kinase inhibition strategy for metastatic recurrent childhood medulloblastoma. J Neurooncol 2023; 163:635-645. [PMID: 37354357 DOI: 10.1007/s11060-023-04372-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/13/2023] [Indexed: 06/26/2023]
Abstract
PURPOSE Medulloblastomas (MBs) constitute the most common malignant brain tumor in children and adolescents. MYC-amplified Group 3 MBs are characterized by disease recurrence, specifically in the leptomeninges, whereby patients with these metastatic tumors have a mortality rate nearing 100%. Despite limited research on such tumors, studies on MB metastases at diagnosis suggest targeting kinases to be beneficial. METHODS To identify kinase inhibitors that eradicate cells driving therapy evasion and tumor dissemination, we utilized our established patient-derived xenograft (PDX) mouse-adapted therapy platform that models human MB metastatic recurrences following standard chemoradiotherapy. High-throughput screens of 640 kinase inhibitors were conducted against cells isolated from mouse spines in the PDX model and human fetal neural stem cells to reveal compounds that targeted these treatment-refractory, metastatic cells, whilst sparing healthy cells. Blood-brain barrier permeability assays and additional in vitro experimentation helped select top candidates for in vivo studies. RESULTS Recurrent Group 3 MB PDX spine cells were therapeutically vulnerable to a selective checkpoint kinase 1 (CHK1) inhibitor and small molecular inhibitor of platelet-derived growth factor receptor beta (PDGFRβ). Inhibitor-treated cells showed a significant reduction in MB stem cell properties associated with treatment failure. Mice also demonstrated survival advantage when treated with a CHK1 inhibitor ex vivo. CONCLUSION We identified CHK1 and PDGFRβ inhibitors that effectively target MB cells fueling treatment-refractory metastases. With limited research on effective therapies for Group 3 MB metastatic recurrences, this work highlights promising therapeutic options to treat these aggressive tumors. Additional studies are warranted to investigate these inhibitors' mechanisms and recommended in vivo administration.
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Affiliation(s)
- Ashley A Adile
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - David Bakhshinyan
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Yujin Suk
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - David Uehling
- Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, M5G 0A3, Canada
| | - Mehakpreet Saini
- Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, M5G 0A3, Canada
| | - Ahmed Aman
- Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, M5G 0A3, Canada
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Jakob Magolan
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Minomi K Subapanditha
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Dillon McKenna
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Chirayu Chokshi
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Neil Savage
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Michelle M Kameda-Smith
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Chitra Venugopal
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Sheila K Singh
- Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
- Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Human Cancer Stem Cell Biology, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Neurosurgey, McMaster Children's Hospital, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
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32
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Ntenti C, Lallas K, Papazisis G. Clinical, Histological, and Molecular Prognostic Factors in Childhood Medulloblastoma: Where Do We Stand? Diagnostics (Basel) 2023; 13:diagnostics13111915. [PMID: 37296767 DOI: 10.3390/diagnostics13111915] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/26/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023] Open
Abstract
Medulloblastomas, highly aggressive neoplasms of the central nervous system (CNS) that present significant heterogeneity in clinical presentation, disease course, and treatment outcomes, are common in childhood. Moreover, patients who survive may be diagnosed with subsequent malignancies during their life or could develop treatment-related medical conditions. Genetic and transcriptomic studies have classified MBs into four subgroups: wingless type (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4, with distinct histological and molecular profiles. However, recent molecular findings resulted in the WHO updating their guidelines and stratifying medulloblastomas into further molecular subgroups, changing the clinical stratification and treatment management. In this review, we discuss most of the histological, clinical, and molecular prognostic factors, as well the feasibility of their application, for better characterization, prognostication, and treatment of medulloblastomas.
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Affiliation(s)
- Charikleia Ntenti
- First Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece
| | - Konstantinos Lallas
- Department of Medical Oncology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece
| | - Georgios Papazisis
- Clinical Research Unit, Special Unit for Biomedical Research and Education (BRESU), School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece
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33
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Cocito C, Martin B, Giantini-Larsen AM, Valcarce-Aspegren M, Souweidane MM, Szalontay L, Dahmane N, Greenfield JP. Leptomeningeal dissemination in pediatric brain tumors. Neoplasia 2023; 39:100898. [PMID: 37011459 PMCID: PMC10124141 DOI: 10.1016/j.neo.2023.100898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 03/09/2023] [Accepted: 03/13/2023] [Indexed: 04/03/2023]
Abstract
Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.
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34
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Mainwaring OJ, Weishaupt H, Zhao M, Rosén G, Borgenvik A, Breinschmid L, Verbaan AD, Richardson S, Thompson D, Clifford SC, Hill RM, Annusver K, Sundström A, Holmberg KO, Kasper M, Hutter S, Swartling FJ. ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors. Nat Commun 2023; 14:1221. [PMID: 36869047 PMCID: PMC9984535 DOI: 10.1038/s41467-023-36847-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.
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Affiliation(s)
- Oliver J Mainwaring
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Holger Weishaupt
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Miao Zhao
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Gabriela Rosén
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Anna Borgenvik
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Laura Breinschmid
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Annemieke D Verbaan
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Stacey Richardson
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK
| | - Dean Thompson
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK
| | - Steven C Clifford
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK
| | - Rebecca M Hill
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK
| | - Karl Annusver
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Anders Sundström
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Karl O Holmberg
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Maria Kasper
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Sonja Hutter
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Fredrik J Swartling
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
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35
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Suthapot P, Chiangjong W, Chaiyawat P, Choochuen P, Pruksakorn D, Sangkhathat S, Hongeng S, Anurathapan U, Chutipongtanate S. Genomics-Driven Precision Medicine in Pediatric Solid Tumors. Cancers (Basel) 2023; 15:1418. [PMID: 36900212 PMCID: PMC10000495 DOI: 10.3390/cancers15051418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 03/12/2023] Open
Abstract
Over the past decades, several study programs have conducted genetic testing in cancer patients to identify potential genetic targets for the development of precision therapeutic strategies. These biomarker-driven trials have demonstrated improved clinical outcomes and progression-free survival rates in various types of cancers, especially for adult malignancies. However, similar progress in pediatric cancers has been slow due to their distinguished mutation profiles compared to adults and the low frequency of recurrent genomic alterations. Recently, increased efforts to develop precision medicine for childhood malignancies have led to the identification of genomic alterations and transcriptomic profiles of pediatric patients which presents promising opportunities to study rare and difficult-to-access neoplasms. This review summarizes the current state of known and potential genetic markers for pediatric solid tumors and provides perspectives on precise therapeutic strategies that warrant further investigations.
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Affiliation(s)
- Praewa Suthapot
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
- Department of Biomedical Science and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Wararat Chiangjong
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Parunya Chaiyawat
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Musculoskeletal Science and Translational Research Center, Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Pongsakorn Choochuen
- Department of Biomedical Science and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
- Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Dumnoensun Pruksakorn
- Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Musculoskeletal Science and Translational Research Center, Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Surasak Sangkhathat
- Department of Biomedical Science and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
- Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
- Department of Surgery, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Usanarat Anurathapan
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Somchai Chutipongtanate
- Division of Epidemiology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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36
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Huss R, Raffler J, Märkl B. Artificial intelligence and digital biomarker in precision pathology guiding immune therapy selection and precision oncology. Cancer Rep (Hoboken) 2023:e1796. [PMID: 36813293 PMCID: PMC10363837 DOI: 10.1002/cnr2.1796] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 01/15/2023] [Accepted: 02/09/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND The currently available immunotherapies already changed the strategy how many cancers are treated from first to last line. Understanding even the most complex heterogeneity in tumor tissue and mapping the spatial cartography of the tumor immunity allows the best and optimized selection of immune modulating agents to (re-)activate the patient's immune system and direct it against the individual cancer in the most effective way. RECENT FINDINGS Primary cancer and metastases maintain a high degree of plasticity to escape any immune surveillance and continue to evolve depending on many intrinsic and extrinsic factors In the field of immune-oncology (IO) immune modulating agents are recognized as practice changing therapeutic modalities. Recent studies have shown that an optimal and lasting efficacy of IO therapeutics depends on the understanding of the spatial communication network and functional context of immune and cancer cells within the tumor microenvironment. Artificial intelligence (AI) provides an insight into the immune-cancer-network through the visualization of very complex tumor and immune interactions in cancer tissue specimens and allows the computer-assisted development and clinical validation of such digital biomarker. CONCLUSIONS The successful implementation of AI-supported digital biomarker solutions guides the clinical selection of effective immune therapeutics based on the retrieval and visualization of spatial and contextual information from cancer tissue images and standardized data. As such, computational pathology (CP) turns into "precision pathology" delivering individual therapy response prediction. Precision Pathology does not only include digital and computational solutions but also high levels of standardized processes in the routine histopathology workflow and the use of mathematical tools to support clinical and diagnostic decisions as the basic principle of a "precision oncology".
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Affiliation(s)
- Ralf Huss
- Medical Faculty University Augsburg, Augsburg, Germany
- Institute for Digital Medicine, University Hospital Augsburg, Augsburg, Germany
| | - Johannes Raffler
- Institute for Digital Medicine, University Hospital Augsburg, Augsburg, Germany
| | - Bruno Märkl
- Medical Faculty University Augsburg, Augsburg, Germany
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37
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Luo Z, Xin D, Liao Y, Berry K, Ogurek S, Zhang F, Zhang L, Zhao C, Rao R, Dong X, Li H, Yu J, Lin Y, Huang G, Xu L, Xin M, Nishinakamura R, Yu J, Kool M, Pfister SM, Roussel MF, Zhou W, Weiss WA, Andreassen P, Lu QR. Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability. Nat Commun 2023; 14:762. [PMID: 36765089 PMCID: PMC9918503 DOI: 10.1038/s41467-023-36400-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 01/30/2023] [Indexed: 02/12/2023] Open
Abstract
MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.
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Affiliation(s)
- Zaili Luo
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Dazhuan Xin
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Yunfei Liao
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Kalen Berry
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Sean Ogurek
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Feng Zhang
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Liguo Zhang
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Chuntao Zhao
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Rohit Rao
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Xinran Dong
- Key Laboratory of Birth Defects, Children's Hospital, Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201102, China
| | - Hao Li
- Key Laboratory of Birth Defects, Children's Hospital, Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201102, China
| | - Jianzhong Yu
- Key Laboratory of Birth Defects, Children's Hospital, Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201102, China
| | - Yifeng Lin
- Key Laboratory of Birth Defects, Children's Hospital, Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201102, China
| | - Guoying Huang
- Key Laboratory of Birth Defects, Children's Hospital, Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201102, China
| | - Lingli Xu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Mei Xin
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Ryuichi Nishinakamura
- Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Jiyang Yu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Marcel Kool
- Hopp Children's Cancer Center Heidelberg (KiTZ); Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Stefan M Pfister
- Hopp Children's Cancer Center Heidelberg (KiTZ); Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
- Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Martine F Roussel
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Wenhao Zhou
- Key Laboratory of Birth Defects, Children's Hospital, Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201102, China.
| | - William A Weiss
- Department of Neurology, Pediatrics, and Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Paul Andreassen
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, 45229, USA
| | - Q Richard Lu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, 45229, USA.
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38
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Villani A, Davidson S, Kanwar N, Lo WW, Li Y, Cohen-Gogo S, Fuligni F, Edward LM, Light N, Layeghifard M, Harripaul R, Waldman L, Gallinger B, Comitani F, Brunga L, Hayes R, Anderson ND, Ramani AK, Yuki KE, Blay S, Johnstone B, Inglese C, Hammad R, Goudie C, Shuen A, Wasserman JD, Venier RE, Eliou M, Lorenti M, Ryan CA, Braga M, Gloven-Brown M, Han J, Montero M, Spatare F, Whitlock JA, Scherer SW, Chun K, Somerville MJ, Hawkins C, Abdelhaleem M, Ramaswamy V, Somers GR, Kyriakopoulou L, Hitzler J, Shago M, Morgenstern DA, Tabori U, Meyn S, Irwin MS, Malkin D, Shlien A. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations. NATURE CANCER 2023; 4:203-221. [PMID: 36585449 PMCID: PMC9970873 DOI: 10.1038/s43018-022-00474-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 11/02/2022] [Indexed: 12/31/2022]
Abstract
We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.
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Affiliation(s)
- Anita Villani
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Scott Davidson
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.,Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Nisha Kanwar
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Winnie W Lo
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Yisu Li
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Sarah Cohen-Gogo
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Fabio Fuligni
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Lisa-Monique Edward
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Nicholas Light
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Mehdi Layeghifard
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Ricardo Harripaul
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Larissa Waldman
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Cancer Genetics and High-Risk Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Bailey Gallinger
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Department of Genetic Counselling, University of Toronto, Toronto, Ontario, Canada.,Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Federico Comitani
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Ledia Brunga
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Reid Hayes
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Nathaniel D Anderson
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Arun K Ramani
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.,Center for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kyoko E Yuki
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Sasha Blay
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Brittney Johnstone
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Cancer Genetics and High-Risk Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Cara Inglese
- Department of Genetic Counselling, University of Toronto, Toronto, Ontario, Canada.,Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rawan Hammad
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Division of Hematology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Catherine Goudie
- Division of Hematology-Oncology, McGill University Health Centre, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Andrew Shuen
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Jonathan D Wasserman
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.,Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rosemarie E Venier
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Department of Genetic Counselling, University of Toronto, Toronto, Ontario, Canada
| | - Marianne Eliou
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Miranda Lorenti
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Carol Ann Ryan
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Michael Braga
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Meagan Gloven-Brown
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jianan Han
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Maria Montero
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Famida Spatare
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - James A Whitlock
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Stephen W Scherer
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada
| | - Kathy Chun
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Martin J Somerville
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Cynthia Hawkins
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Mohamed Abdelhaleem
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Vijay Ramaswamy
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Gino R Somers
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Lianna Kyriakopoulou
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Johann Hitzler
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Mary Shago
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Daniel A Morgenstern
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Uri Tabori
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Stephen Meyn
- Center for Human Genomics and Precision Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Meredith S Irwin
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - David Malkin
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. .,Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. .,Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
| | - Adam Shlien
- Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. .,Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
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Okonechnikov K, Federico A, Schrimpf D, Sievers P, Sahm F, Koster J, Jones DTW, von Deimling A, Pfister SM, Kool M, Korshunov A. Comparison of transcriptome profiles between medulloblastoma primary and recurrent tumors uncovers novel variance effects in relapses. Acta Neuropathol Commun 2023; 11:7. [PMID: 36635768 PMCID: PMC9837941 DOI: 10.1186/s40478-023-01504-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 12/27/2022] [Indexed: 01/13/2023] Open
Abstract
Nowadays medulloblastoma (MB) tumors can be treated with risk-stratified approaches with up to 80% success rate. However, disease relapses occur in approximately 30% of patients and successful salvage treatment strategies at relapse remain scarce. Acquired copy number changes or TP53 mutations are known to occur frequently in relapses, while methylation profiles usually remain highly similar to those of the matching primary tumors, indicating that in general molecular subgrouping does not change during the course of the disease. In the current study, we have used RNA sequencing data to analyze the transcriptome profiles of 43 primary-relapse MB pairs in order to identify specific molecular features of relapses within various tumor groups. Gene variance analysis between primary and relapse samples demonstrated the impact of age in SHH-MB: the changes in gene expression relapse profiles were more pronounced in the younger patients (< 10 years old), which were also associated with increased DNA aberrations and somatic mutations at relapse probably driving this effect. For Group 3/4 MB transcriptome data analysis uncovered clear sets of genes either active or decreased at relapse that are significantly associated with survival, thus could be potential predictive markers. In addition, deconvolution analysis of bulk transcriptome data identified progression-associated differences in cell type enrichment. The proportion of undifferentiated progenitors increased in SHH-MB relapses with a concomitant decrease of differentiated neuron-like cells, while in Group 3/4 MB relapses cell cycle activity increases and differentiated neuron-like cells proportion decreases as well. Thus, our findings uncovered significant transcriptome changes in the molecular signatures of relapsed MB and could be potentially useful for further clinical purposes.
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Affiliation(s)
- Konstantin Okonechnikov
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Aniello Federico
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Daniel Schrimpf
- grid.7497.d0000 0004 0492 0584Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.5253.10000 0001 0328 4908Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Philipp Sievers
- grid.7497.d0000 0004 0492 0584Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.5253.10000 0001 0328 4908Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Felix Sahm
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.5253.10000 0001 0328 4908Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jan Koster
- grid.7177.60000000084992262Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam and Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - David T. W. Jones
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas von Deimling
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.5253.10000 0001 0328 4908Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan M. Pfister
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.5253.10000 0001 0328 4908Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Marcel Kool
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.487647.ePrincess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Andrey Korshunov
- grid.510964.fHopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ,grid.5253.10000 0001 0328 4908Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
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Chen Z, Yang H, Wang J, Long G, Xi Q, Chen T, He Y, Zhang B, Wan F. Molecular characterization of sub-frontal recurrent medulloblastomas reveals potential clinical relevance. Front Neurol 2023; 14:1148848. [PMID: 37181548 PMCID: PMC10173865 DOI: 10.3389/fneur.2023.1148848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/28/2023] [Indexed: 05/16/2023] Open
Abstract
Background Single recurrence in the sub-frontal region after cerebellar medulloblastoma (MB) resection is rare and the underlying molecular characteristics have not been specifically addressed. Methods We summarized two such cases in our center. All five samples were molecularly profiled for their genome and transcriptome signatures. Results The recurrent tumors displayed genomic and transcriptomic divergence. Pathway analysis of recurrent tumors showed functional convergence in metabolism, cancer, neuroactive ligand-receptor interaction, and PI3K-AKT signaling pathways. Notably, the sub-frontal recurrent tumors had a much higher proportion (50-86%) of acquired driver mutations than that reported in other recurrent locations. The acquired putative driver genes in the sub-frontal recurrent tumors functionally enriched for chromatin remodeler-associated genes, such as KDM6B, SPEN, CHD4, and CHD7. Furthermore, the germline mutations of our cases showed a significant functional convergence in focal adhesion, cell adhesion molecules, and ECM-receptor interaction. Evolutionary analysis showed that the recurrence could be derived from a single primary tumor lineage or had an intermediate phylogenetic similarity to the matched primary one. Conclusion Rare single sub-frontal recurrent MBs presented specific mutation signatures that might be related to the under-dose radiation. Particular attention should be paid to optimally covering the sub-frontal cribriform plate during postoperative radiotherapy targeting.
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Affiliation(s)
- Zirong Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huaitao Yang
- Department of Neurosurgery, Jingzhou Central Hospital, Jingzhou, China
| | - Jiajia Wang
- Department of Pediatric Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guoxian Long
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingsong Xi
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Chen
- Department of Neurosurgery, Jingzhou Central Hospital, Jingzhou, China
| | - Yue He
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Zhang
- Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Bin Zhang
| | - Feng Wan
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Feng Wan
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Marquardt V, Theruvath J, Pauck D, Picard D, Qin N, Blümel L, Maue M, Bartl J, Ahmadov U, Langini M, Meyer FD, Cole A, Cruz-Cruz J, Graef CM, Wölfl M, Milde T, Witt O, Erdreich-Epstein A, Leprivier G, Kahlert U, Stefanski A, Stühler K, Keir ST, Bigner DD, Hauer J, Beez T, Knobbe-Thomsen CB, Fischer U, Felsberg J, Hansen FK, Vibhakar R, Venkatraman S, Cheshier SH, Reifenberger G, Borkhardt A, Kurz T, Remke M, Mitra S. Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation. J Immunother Cancer 2023; 11:jitc-2022-005871. [PMID: 36639156 PMCID: PMC9843227 DOI: 10.1136/jitc-2022-005871] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway. METHODS We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models. RESULTS CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice. CONCLUSION Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
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Affiliation(s)
- Viktoria Marquardt
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Johanna Theruvath
- Department of Neurosurgery, Institute for StemCell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - David Pauck
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Daniel Picard
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Nan Qin
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Lena Blümel
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Mara Maue
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Jasmin Bartl
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Ulvi Ahmadov
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Maike Langini
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany
| | - Frauke-Dorothee Meyer
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Allison Cole
- Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
| | | | - Claus M Graef
- Department of Neurosurgery, Institute for StemCell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA
| | - Matthias Wölfl
- Department of Pediatric Oncology, University Children's Hospital Würzburg, Würzburg, Germany
| | - Till Milde
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Olaf Witt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Anat Erdreich-Epstein
- Division of Hematology-Oncology and Blood and Marrow Transplantation, Department of Pediatrics and the Department of Pathology, Children's Hospital Los Angeles, and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Gabriel Leprivier
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Ulf Kahlert
- Department of Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Anja Stefanski
- Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany
| | - Stephen T Keir
- Department of Neurosurgery, Duke University, Durham, North Carolina, USA
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| | - Darell D Bigner
- Department of Neurosurgery, Duke University, Durham, North Carolina, USA
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| | - Julia Hauer
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Thomas Beez
- Department of Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Christiane B Knobbe-Thomsen
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Ute Fischer
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Jörg Felsberg
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Finn K Hansen
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Leipzig, Germany
| | - Rajeev Vibhakar
- Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
| | | | - Samuel H Cheshier
- Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Guido Reifenberger
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Arndt Borkhardt
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Thomas Kurz
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Marc Remke
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Siddhartha Mitra
- Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
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Borgenvik A, Holmberg KO, Bolin S, Zhao M, Savov V, Rosén G, Hutter S, Garancher A, Rahmanto AS, Bergström T, Olsen TK, Mainwaring OJ, Sattanino D, Verbaan AD, Rusert JM, Sundström A, Bravo MB, Dang Y, Wenz AS, Richardson S, Fotaki G, Hill RM, Dubuc AM, Kalushkova A, Remke M, Čančer M, Jernberg-Wiklund H, Giraud G, Chen X, Taylor MD, Sangfelt O, Clifford SC, Schüller U, Wechsler-Reya RJ, Weishaupt H, Swartling FJ. Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma. Cancer Res 2022; 82:4586-4603. [PMID: 36219398 PMCID: PMC9755969 DOI: 10.1158/0008-5472.can-22-2108] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/01/2022] [Accepted: 10/07/2022] [Indexed: 01/24/2023]
Abstract
Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. SIGNIFICANCE SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
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Affiliation(s)
- Anna Borgenvik
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Karl O. Holmberg
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Sara Bolin
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Miao Zhao
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Vasil Savov
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Gabriela Rosén
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Sonja Hutter
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Alexandra Garancher
- Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California
| | | | - Tobias Bergström
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Thale Kristin Olsen
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Oliver J. Mainwaring
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Damiana Sattanino
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Annemieke D. Verbaan
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Jessica M. Rusert
- Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California
| | - Anders Sundström
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Mar Ballester Bravo
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Yonglong Dang
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden
| | - Amelie S. Wenz
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden
| | - Stacey Richardson
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
| | - Grammatiki Fotaki
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Rebecca M. Hill
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
| | - Adrian M. Dubuc
- The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Antonia Kalushkova
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Marc Remke
- The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Matko Čančer
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Helena Jernberg-Wiklund
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Géraldine Giraud
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Xingqi Chen
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden
| | - Michael D. Taylor
- The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Olle Sangfelt
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Steven C. Clifford
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
| | - Ulrich Schüller
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Paediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
| | - Robert J. Wechsler-Reya
- Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California
| | - Holger Weishaupt
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Fredrik J. Swartling
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.,Corresponding Author: Fredrik J. Swartling, Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala 751 85, Sweden. E-mail:
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43
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Stankunaite R, Marshall LV, Carceller F, Chesler L, Hubank M, George SL. Liquid biopsy for children with central nervous system tumours: Clinical integration and technical considerations. Front Pediatr 2022; 10:957944. [PMID: 36467471 PMCID: PMC9709284 DOI: 10.3389/fped.2022.957944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Circulating cell-free DNA (cfDNA) analysis has the potential to revolutionise the care of patients with cancer and is already moving towards standard of care in some adult malignancies. Evidence for the utility of cfDNA analysis in paediatric cancer patients is also accumulating. In this review we discuss the limitations of blood-based assays in patients with brain tumours and describe the evidence supporting cerebrospinal fluid (CSF) cfDNA analysis. We make recommendations for CSF cfDNA processing to aid the standardisation and technical validation of future assays. We discuss the considerations for interpretation of cfDNA analysis and highlight promising future directions. Overall, cfDNA profiling shows great potential as an adjunct to the analysis of biopsy tissue in paediatric cancer patients, with the potential to provide a genetic molecular profile of the tumour when tissue biopsy is not feasible. However, to fully realise the potential of cfDNA analysis for children with brain tumours larger prospective studies incorporating serial CSF sampling are required.
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Affiliation(s)
- Reda Stankunaite
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
- Clinical Genomics, Royal Marsden NHS Foundation Trust, London, United Kingdom
- Evolutionary Genomics and Modelling, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Lynley V. Marshall
- Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Fernando Carceller
- Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Louis Chesler
- Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Michael Hubank
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
- Clinical Genomics, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Sally L. George
- Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
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44
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Schoen LF, Craveiro RB, Pietsch T, Moritz T, Troeger A, Jordans S, Dilloo D. The
PI3K
inhibitor pictilisib and the multikinase inhibitors pazopanib and sorafenib have an impact on Rac1 level and migration of medulloblastoma in vitro. J Cell Mol Med 2022; 26:5832-5845. [DOI: 10.1111/jcmm.17604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 09/24/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Leonie F. Schoen
- Department of Pediatric Hematology and Oncology, Center for Pediatrics University Hospital Bonn Bonn Germany
| | | | - Torsten Pietsch
- Department of Neuropathology University Hospital Bonn Bonn Germany
| | - Thomas Moritz
- Institute of Experimental Hematology Hannover Medical School Hannover Germany
| | - Anja Troeger
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation University Hospital Regensburg Regensburg Germany
| | - Silvia Jordans
- Department of Pediatric Hematology and Oncology, Center for Pediatrics University Hospital Bonn Bonn Germany
| | - Dagmar Dilloo
- Department of Pediatric Hematology and Oncology, Center for Pediatrics University Hospital Bonn Bonn Germany
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45
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Xu Z, Murad N, Malawsky D, Tao R, Rivero-Hinojosa S, Holdhof D, Schüller U, Zhang P, Lazarski C, Rood BR, Packer R, Gershon T, Pei Y. OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma. Clin Cancer Res 2022; 28:4278-4291. [PMID: 35736214 PMCID: PMC9529814 DOI: 10.1158/1078-0432.ccr-22-0527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/10/2022] [Accepted: 05/24/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence, thus new therapeutic approaches to prevent recurrence are needed. EXPERIMENTAL DESIGN We evaluated OLIG2 expression in a panel of mouse Myc-driven MB tumors, patient MB samples, and patient-derived xenograft (PDX) tumors and analyzed radiation sensitivity in OLIG2-high and OLIG2-low tumors in PDX lines. We assessed the effect of inhibition of OLIG2 by OLIG2-CRISPR or the small molecule inhibitor CT-179 combined with radiotherapy on tumor progression in PDX models. RESULTS We found that MYC-associated MB can be stratified into OLIG2-high and OLIG2-low tumors based on OLIG2 protein expression. In MYC-amplified MB PDX models, OLIG2-low tumors were sensitive to radiation and rarely relapsed, whereas OLIG2-high tumors were resistant to radiation and consistently developed recurrence. In OLIG2-high tumors, irradiation eliminated the bulk of tumor cells; however, a small number of tumor cells comprising OLIG2- tumor cells and rare OLIG2+ tumor cells remained in the cerebellar tumor bed when examined immediately post-irradiation. All animals harboring residual-resistant tumor cells developed relapse. The relapsed tumors mirrored the cellular composition of the primary tumors with enriched OLIG2 expression. Further studies demonstrated that OLIG2 was essential for recurrence, as OLIG2 disruption with CRISPR-mediated deletion or with the small molecule inhibitor CT-179 prevented recurrence from the residual radioresistant tumor cells. CONCLUSIONS Our studies reveal that OLIG2 is a biomarker and an effective therapeutic target in a high-risk subset of MYC-amplified MB, and OLIG2 inhibitor combined with radiotherapy represents a novel effective approach for treating this devastating disease.
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Affiliation(s)
- Zhenhua Xu
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
| | - Najiba Murad
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
| | - Daniel Malawsky
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Ran Tao
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Samuel Rivero-Hinojosa
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
| | - Dörthe Holdhof
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20251, Germany
- Research Institute Children’s Cancer Center, Martinistraße 52, Hamburg 20251, Germany
| | - Ulrich Schüller
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20251, Germany
- Research Institute Children’s Cancer Center, Martinistraße 52, Hamburg 20251, Germany
- Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20251, Germany
| | - Peng Zhang
- Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100069, China
| | - Christopher Lazarski
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
| | - Brian R. Rood
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
| | - Roger Packer
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
| | - Timothy Gershon
- Department of Neurology, University North Carolina, School of Medicine, Chapel Hill, NC 27516, USA
| | - Yanxin Pei
- Center for Cancer and Immunology, Brain Tumor Institute, Children’s National Health System, Washington, DC 20010, USA
- Lead contact
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46
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Zhang ZW, Teng X, Zhao F, Ma C, Zhang J, Xiao LF, Wang Y, Chang M, Tian Y, Li C, Zhang Z, Song S, Tong WM, Liu P, Niu Y. METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma. Cell Rep 2022; 41:111530. [DOI: 10.1016/j.celrep.2022.111530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 07/31/2022] [Accepted: 09/28/2022] [Indexed: 11/30/2022] Open
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47
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Williamson D, Schwalbe EC, Hicks D, Aldinger KA, Lindsey JC, Crosier S, Richardson S, Goddard J, Hill RM, Castle J, Grabovska Y, Hacking J, Pizer B, Wharton SB, Jacques TS, Joshi A, Bailey S, Clifford SC. Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development. Cell Rep 2022; 40:111162. [PMID: 35926460 PMCID: PMC9638015 DOI: 10.1016/j.celrep.2022.111162] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 05/26/2022] [Accepted: 07/13/2022] [Indexed: 01/29/2023] Open
Abstract
Medulloblastoma is currently subclassified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA sequencing (RNA-seq) in large, well-annotated cohorts of medulloblastoma, we show that transcriptionally group 3 and group 4 medulloblastomas exist as intermediates on a bipolar continuum between archetypal group 3 and group 4 entities. Continuum position is prognostic, reflecting a propensity for specific DNA copy-number changes, and specific switches in isoform/enhancer usage and RNA editing. Examining single-cell RNA-seq (scRNA-seq) profiles, we show that intratumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas, we show that this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify distinct developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of group 3/group 4 molecular biology and clinico-pathology.
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Affiliation(s)
- Daniel Williamson
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK.
| | - Edward C. Schwalbe
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK,Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK
| | - Debbie Hicks
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Kimberly A. Aldinger
- Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Janet C. Lindsey
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Stephen Crosier
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Stacey Richardson
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Jack Goddard
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Rebecca M. Hill
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Jemma Castle
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Yura Grabovska
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK,Division of Molecular Pathology, Institute of Cancer Research, London, UK
| | - James Hacking
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Barry Pizer
- Institute of Translational Research, University of Liverpool, Liverpool, UK
| | - Stephen B. Wharton
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Thomas S. Jacques
- Developmental Biology and Cancer Programme, UCL GOS Institute of Child Health, London, and Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Abhijit Joshi
- Department of Neuropathology, Royal Victoria Infirmary (RVI), Newcastle University Teaching Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Simon Bailey
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Steven C. Clifford
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK,Corresponding author
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48
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Chen Y, Liu H, Zheng Q, Li H, You H, Feng Y, Feng W. Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin. Life Sci 2022; 306:120826. [PMID: 35870618 DOI: 10.1016/j.lfs.2022.120826] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/09/2022] [Accepted: 07/15/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND AND OBJECTIVES There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated. METHODS Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues. RESULTS The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells. CONCLUSIONS These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents. MAJOR FINDING This study observes a previously neglected pharmacological phenomenon and investigates its mechanism of that the continuous low-dose administration of some antineoplastic agents in certain dose ranges can promote tumorigenesis and tumor progression in vitro and in vivo, through stimulation of tumor cell functions directly as well as enhancement of tumor angiogenesis by BMDCs recruitment indirectly. The results alert to a potential risk in current empirically based continuous low-dose chemotherapy regimens such as metronomic chemotherapy.
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Affiliation(s)
- Yanshen Chen
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China; Department of Pharmacy, Jiangsu Vocational College of Medicine, Jiefang South Road 283 th, Yancheng 224005, Jiangsu, PR China
| | - Hua Liu
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Qiaowei Zheng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Houli Li
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Huining You
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Yan Feng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Weiyi Feng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China.
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49
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Parakh S, Davies A, Westcott K, Roos D, Abou-Hamden A, Ahern E, Lau PKH, Cheruvu S, Pranavan G, Pullar A, Lynam J, Gzell C, Whittle JR, Cain S, Inglis PL, Harrup R, Anazodo A, Hovey E, Cher L, Gan HK. Adult medulloblastoma in an Australian population. J Clin Neurosci 2022; 102:65-70. [PMID: 35728397 DOI: 10.1016/j.jocn.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/10/2022] [Accepted: 06/13/2022] [Indexed: 11/16/2022]
Abstract
Medulloblastoma in adult patients is a rare condition with limited contemporary demographic and treatment outcome data available in an Australian population. We conducted a retrospective review of patterns of care and outcomes of adult patients diagnosed with medulloblastoma treated at major neuro-oncology centres across Australia between January 2010 and December 2019. A total of 80 patients were identified and the median follow-up after diagnosis was 59.2 (range 0.5-204) months. A variety of chemotherapy regimens were used in the adjuvant and recurrent settings. The median overall survival (mOS) was 78 months (IQR 17.5-94.8). Patients who had no residual disease post-resection or with SHH-subtype tumours had a numerically longer 5-year survival rate than those with residual disease post resection or non-SHH subtypes respectively. The median time to recurrence from diagnosis was 18.4 months. The median OS from 1st relapse was 22.1 months (95% CI 11.7-31.4) and mOS from second relapse was 10.2 months (95% CI 6.6 - NR). This is the largest dataset examining patterns of care of adult patients with medulloblastoma in an Australian population. Substantial variation existed in the chemotherapy agents used in the adjuvant and recurrent setting. As has been demonstrated in a paediatric population, trials such as the upcoming EORTC 1634-BTG/NOA-23 trial (PersoMed-1 study) which are tailoring treatments to molecular profiles are likely to improve outcome in adult medulloblastoma.
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Affiliation(s)
- Sagun Parakh
- Olivia Newton John Cancer Research Institute, Melbourne, Australia; Austin Health, Melbourne, Australia; La Trobe University, School of Cancer Medicine, Heidelberg, Victoria, Australia.
| | | | - Kerryn Westcott
- Olivia Newton John Cancer Research Institute, Melbourne, Australia
| | - Daniel Roos
- Royal Adelaide Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia
| | - Amal Abou-Hamden
- Royal Adelaide Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia
| | - Elizabeth Ahern
- Monash Health, Melbourne, Australia; Monash University, Melbourne, Australia
| | | | | | - Ganesalingam Pranavan
- The Canberra Hospital, Canberra, Australia; The Australian National University, Canberra, Australia
| | | | - James Lynam
- Calvary Mater Newcastle, Newcastle, Australia; University of Newcastle, Newcastle, Australia
| | | | - James R Whittle
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia; Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Sarah Cain
- Royal Melbourne Hospital, Melbourne, Australia
| | - Po-Ling Inglis
- Royal Brisbane and Women's Hospital, Brisbane, Australia
| | | | - Antoinette Anazodo
- Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, Australia
| | - Elizabeth Hovey
- Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, Australia; Faculty of Medicine, The University of New South Wales
| | | | - Hui K Gan
- Olivia Newton John Cancer Research Institute, Melbourne, Australia; Austin Health, Melbourne, Australia; La Trobe University, School of Cancer Medicine, Heidelberg, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia
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50
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Giannikopoulos P, Parham DM. Pediatric Sarcomas: The Next Generation of Molecular Studies. Cancers (Basel) 2022; 14:2515. [PMID: 35626119 PMCID: PMC9139929 DOI: 10.3390/cancers14102515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 05/13/2022] [Indexed: 02/04/2023] Open
Abstract
Pediatric sarcomas constitute one of the largest groups of childhood cancers, following hematopoietic, neural, and renal lesions. Partly because of their diversity, they continue to offer challenges in diagnosis and treatment. In spite of the diagnostic, nosologic, and therapeutic gains made with genetic technology, newer means for investigation are needed. This article reviews emerging technology being used to study human neoplasia and how these methods might be applicable to pediatric sarcomas. Methods reviewed include single cell RNA sequencing (scRNAseq), spatial multi-omics, high-throughput functional genomics, and clustered regularly interspersed short palindromic sequence-Cas9 (CRISPR-Cas9) technology. In spite of these advances, the field continues to be challenged by a dearth of properly annotated materials, particularly from recurrences and metastases and pre- and post-treatment samples.
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Affiliation(s)
| | - David M. Parham
- Department of Anatomic Pathology, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
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