|
1
|
Dhar SS, Brown C, Rizvi A, Reed L, Kotla S, Zod C, Abraham J, Abe JI, Rajaram V, Chen K, Lee MG. Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS. Cell Rep 2025; 44:115619. [PMID: 40286267 DOI: 10.1016/j.celrep.2025.115619] [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: 07/10/2024] [Revised: 02/17/2025] [Accepted: 04/04/2025] [Indexed: 04/29/2025] Open
Abstract
The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in many cancers, including medulloblastoma (MB). Notably, heterozygous KMT2D loss frequently occurs in MB and other cancers. However, its oncogenic role remains largely uncharacterized. Here, we show that heterozygous Kmt2d loss in murine cerebellar regions promotes MB genesis driven by heterozygous loss of the MB-suppressor gene Ptch via the upregulation of tumor-promoting programs (e.g., oxidative phosphorylation [OXPHOS]). Downregulation of the transcription-repressive tumor suppressor NCOR2 by heterozygous Kmt2d loss, along with Ptch+/--increased MYCN, upregulated tumor-promoting genes. Heterozygous Kmt2d loss substantially diminished enhancer marks (H3K4me1 and H3K27ac) and the H3K4me3 signature, including those for Ncor2. Combinatory pharmacological inhibition of the enhancer-decommissioning H3K4 demethylase LSD1 and OXPHOS significantly reduced the tumorigenicity of MB cells bearing heterozygous Kmt2d loss. Our findings suggest the molecular and epigenetic pathogenesis underlying the MB-promoting effect of heterozygous KMT2D loss.
Collapse
Affiliation(s)
- Shilpa S Dhar
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
| | - Calena Brown
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Ali Rizvi
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Lauren Reed
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Constantin Zod
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Janak Abraham
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Jun-Ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Veena Rajaram
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
| | - Kaifu Chen
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Min Gyu Lee
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
| |
Collapse
|
|
2
|
Trussina IREA, Hartmann A, Desroches Altamirano C, Natarajan J, Fischer CM, Aleksejczuk M, Ausserwöger H, Knowles TPJ, Schlierf M, Franzmann TM, Alberti S. G3BP-driven RNP granules promote inhibitory RNA-RNA interactions resolved by DDX3X to regulate mRNA translatability. Mol Cell 2025; 85:585-601.e11. [PMID: 39729994 DOI: 10.1016/j.molcel.2024.11.039] [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: 06/03/2024] [Revised: 10/08/2024] [Accepted: 11/27/2024] [Indexed: 12/29/2024]
Abstract
Ribonucleoprotein (RNP) granules have been linked to translation regulation and disease, but their assembly and regulatory mechanisms are not well understood. Here, we show that the RNA-binding protein G3BP1 preferentially interacts with unfolded RNA, driving the assembly of RNP granule-like condensates that establish RNA-RNA interactions. These RNA-RNA interactions limit the mobility and translatability of sequestered mRNAs and stabilize the condensates. The DEAD-box RNA helicase DDX3X attenuates RNA-RNA interactions inside RNP granule-like condensates, rendering the condensates dynamic and enabling mRNA translation. Importantly, disease-associated and catalytically inactive DDX3X variants fail to resolve such RNA-RNA interactions. Inhibiting DDX3X in cultured cells accelerates RNP granule assembly and delays their disassembly, indicating that RNA-RNA interactions contribute to RNP granule stability in cells. Our findings reveal how RNP granules generate inhibitory RNA-RNA interactions that are modulated by DEAD-box RNA helicases to ensure RNA availability and translatability.
Collapse
Affiliation(s)
- Irmela R E A Trussina
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany
| | - Andreas Hartmann
- B CUBE Center for Molecular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany
| | | | - Janani Natarajan
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany
| | - Charlotte M Fischer
- Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge CB2 1EW, UK
| | - Marta Aleksejczuk
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany
| | - Hannes Ausserwöger
- Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge CB2 1EW, UK
| | - Tuomas P J Knowles
- Yusuf Hamied Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge CB2 1EW, UK
| | - Michael Schlierf
- B CUBE Center for Molecular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany; Cluster of Excellence Physics of Life, TU Dresden, Dresden 01307 Saxony, Germany
| | - Titus M Franzmann
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany
| | - Simon Alberti
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden 01307 Saxony, Germany; Cluster of Excellence Physics of Life, TU Dresden, Dresden 01307 Saxony, Germany.
| |
Collapse
|
|
3
|
Cong G, Zhu X, Chen XR, Chen H, Chong W. Mechanisms and therapeutic potential of the hedgehog signaling pathway in cancer. Cell Death Discov 2025; 11:40. [PMID: 39900571 PMCID: PMC11791101 DOI: 10.1038/s41420-025-02327-w] [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: 10/31/2024] [Revised: 12/25/2024] [Accepted: 01/24/2025] [Indexed: 02/05/2025] Open
Abstract
A sort of major malignant disease, cancer can compromise human health wherever. Some mechanisms of the occurrence and evolution of cancer still seem elusive even now. Consequently, the therapeutic strategies for cancer must continually evolve. The hedgehog signaling pathway, a critical mediator in the normal development of numerous organs and the pathogenesis of cancer, is typically quiescent but is aberrantly activated in several malignancies. Extensive research has delineated that the aberrant activity of the hedgehog signaling pathway, whether autocrine or paracrine, is implicated in the initiation and progression of various neoplasms, including medulloblastoma (MB), basal cell carcinoma (BCC) and so on. Thus, notably Smo inhibitors, the opening of inhibitors of the hedgehog signaling pathway has become a topic of research attention. This review aims to summarize four aberrant activation pathways and the influence of hedgehog signaling pathway associated chemicals on tumor formation and development. Additionally, it will explore the therapeutic potential of targeted interventions in the hedgehog signaling pathway for cancer treatment.
Collapse
Affiliation(s)
- Ge Cong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China
| | - Xingyu Zhu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China
| | - Xin Ru Chen
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China
| | - Hao Chen
- Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, 250021, Jinan, China.
| | - Wei Chong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China.
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China.
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China.
| |
Collapse
|
|
4
|
Fang R, Wang X, Wu R, Pan R, Tian M, Zhang R, Wei X, Wang X, Ye S, Li F, Xia Q, Cheng Y, Rao Q. SMARCA4/BRG1 deficiency induces a targetable dependence on oxidative phosphorylation in clear cell renal cell carcinoma. Carcinogenesis 2025; 46:bgaf002. [PMID: 39851260 DOI: 10.1093/carcin/bgaf002] [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: 06/13/2024] [Revised: 01/03/2025] [Accepted: 01/17/2025] [Indexed: 01/26/2025] Open
Abstract
The tumor suppressor gene SMARCA4, a critical component of the SWI/SNF chromatin remodeling complex, is frequently inactivated in various cancers, including clear cell renal cell carcinoma (ccRCC). Despite its significance, the role of SMARCA4 in ccRCC development and its potential therapeutic vulnerabilities have not been fully explored. Our research found that SMARCA4 deficiency was associated with poor prognosis and was observed in a subset of high-grade ccRCCs. Through functional assays, we determined that the suppression of SMARCA4 led to an increase in RCC cell proliferation. Further gene expression analysis unveiled that SMARCA4-deficient cells exhibit an upregulation of the oxidative phosphorylation (OXPHOS) pathway. Delving deeper, we combined RNA sequencing (RNA-Seq) and Assay for transposase-accessible chromatin with sequencing (ATAC-Seq) data to uncover that SMARCA4 plays a crucial role in modulating chromatin accessibility and the expression of genes essential for the respiratory electron transport chain. A significant finding from our study is that RCC cells and xenograft tumors lacking SMARCA4 demonstrated an increased sensitivity to the inhibition of the OXPHOS pathway by the novel small molecule IACS-010759. This sensitivity is attributed to the heightened energy demands and susceptibility to energy stress observed in SMARCA4-deficient cells, driven by their amplified biosynthetic requirements. The efficacy of IACS-010759 stems from its ability to induce energy deprivation, pinpointing OXPHOS inhibition as a promising therapeutic approach for targeting SMARCA4-mutant tumors. This strategy offers a novel avenue to address a currently unmet therapeutic need, highlighting the potential of OXPHOS inhibition in the treatment of cancers harboring SMARCA4 mutations.
Collapse
Affiliation(s)
- Ru Fang
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Xiaotong Wang
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Ruina Wu
- Jinling Clinical Medical College, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Rui Pan
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Miaomiao Tian
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Rusong Zhang
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Xue Wei
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Xuan Wang
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Shengbing Ye
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Feng Li
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, China
| | - Qiuyuan Xia
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
| | - Yang Cheng
- Center for Health Management, Jiangsu Province Geriatric Hospital, 2 Yi-He Road, Nanjing, 210024, China
| | - Qiu Rao
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Nanjing, 210002, China
- Jinling Clinical Medical College, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| |
Collapse
|
|
5
|
Han D, Jin X, Li J. Genomic landscape of medulloblastoma subtypes in an Asian cohort. Transl Cancer Res 2024; 13:6721-6731. [PMID: 39816537 PMCID: PMC11730696 DOI: 10.21037/tcr-24-1350] [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: 08/03/2024] [Accepted: 10/31/2024] [Indexed: 01/18/2025]
Abstract
Background Medulloblastoma (MB) is a highly malignant childhood brain tumor. Previous research on the genetic underpinnings of MB subtypes has predominantly focused on European and American cohorts. Given the notable genetic differences between Asian and other populations, a subtype-specific study on an Asian cohort is essential to provide comprehensive insights into MB within this demographic. The aim of this study is to investigate the genomic landscape of MB subtypes in an Asian cohort to better understand the genetic variations and potential implications for clinical practice. Methods We conducted a study on an Asian cohort comprising 113 MB patients. Genomic sequencing was performed using MGISEQ-2000 platform. We analyzed the participants' characteristics and compared them with previous studies. All germline variants of the ten susceptibility genes of interest (APC, BRCA2, PTCH1, PTCH2, ELP1, SUFU, CTNNB1, SMARCA4, GPR161, and TP53) were annotated and validated. Results Our study identified 14 valid germline variants that met our criteria, with these variants being detected in the genes APC, BRCA2, PTCH1, PTCH2, ELP1, and SUFU. Of these, six variants were classified as pathogenic in ClinVar: two in PTCH2 (c.C1573T), one in ELP1 (c.C583T), and three in PTCH1 (c.G1370T, c.C2066T, c.C529T). The remaining eight variants were of uncertain significance, including those in SUFU (c.T833C), ELP1 (c.T2A), BRCA2 (c.G7488C), and APC (c.C3247A, c.A1G, c.A8042G, c.A3056G, c.G822C). Our findings highlight a subtype-based germline variant landscape specific to the Asian cohort and reinforce the connection between SUFU, PTCH1, and the SHH subtype of MB. Additionally, the identification of ELP1-related cases supports the newest findings in this area and provides typical copy number variation (CNV) results for future investigation. Conclusions This study provides valuable insights into the genetic landscape of MB in an Asian cohort, emphasizing the importance of population-specific research. The subtype-specific germline variant landscape identified in this study contributes to the understanding of MB and its genetic underpinnings in Asian populations, potentially guiding future research and therapeutic strategies.
Collapse
Affiliation(s)
- Dongming Han
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI Research, Chongqing, China
| | - Xin Jin
- BGI Research, Chongqing, China
| | | |
Collapse
|
|
6
|
Nguyen AL, Facey COB, Boman BM. The Significance of Aldehyde Dehydrogenase 1 in Cancers. Int J Mol Sci 2024; 26:251. [PMID: 39796106 PMCID: PMC11720537 DOI: 10.3390/ijms26010251] [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: 11/14/2024] [Revised: 12/16/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
The goal of this paper is to discuss the role of ALDH isozymes in different cancers, review advances in ALDH1-targeting cancer therapies, and explore a mechanism that explains how ALDH expression becomes elevated during cancer development. ALDH is often overexpressed in cancer, and each isoform has a unique expression pattern and a distinct role in different cancers. The abnormal expression of ALDHs in different cancer types (breast, colorectal, lung, gastric, cervical, melanoma, prostate, and renal) is presented and correlated with patient prognosis. ALDH plays a significant role in various cellular functions, such as metabolism, oxidative stress response, detoxification, and cellular differentiation. Among the ALDH families, ALDH1 has gained considerable attention as a cancer stem cell (CSC) marker due to its significant role in the maintenance of stemness and the differentiation of stem cells (SCs), along with its involvement in tumorigenesis. A description of the cellular mechanisms and physiology of ALDH1 that underlies cancer development is provided. Moreover, current advances in ALDH1-targeting cancer therapies are discussed.
Collapse
Affiliation(s)
- Anh L. Nguyen
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA;
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA;
| | - Bruce M. Boman
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA;
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
7
|
Dave B, Tailor J. Human stem cell models to unravel brain cancer. BMC Cancer 2024; 24:1465. [PMID: 39609728 PMCID: PMC11603633 DOI: 10.1186/s12885-024-13187-5] [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: 02/08/2024] [Accepted: 11/11/2024] [Indexed: 11/30/2024] Open
Abstract
Pre-clinical animal models of human brain tumors have been invaluable tools for studying cancer pathogenesis and exploring novel treatment modalities. Such models recapitulate important aspects of the human disease such as the stem-progenitor-differentiated cell hierarchy. Although powerful, we argue that animal models are inherently limited in their ability to phenocopy certain important aspects of human brain tumor biology. We specifically highlight the inability of mouse models to generate certain forms aggressive pediatric medulloblastoma likely owing to cellular, anatomic, and genetic differences between the human and mouse brains. Additionally, we review some limitations of human brain tumor derived cell lines and outline why they are a sub-optimal system for purposes of pre-clinical modeling. Below, we present the case for human stem cell-based models of brain tumors, focusing mainly on glioblastoma and medulloblastoma. Drawing on several recently published studies, we review the exciting progress that has been made towards modeling human brain tumors using two-dimensional adherent stem cell cultures and three-dimensional organoids. We identify the important advances arrived at using these human stem cell-based models and suggest opportunities for future work in this direction. In this review article, we aim to highlight the utility and promises of human stem cell-based models of brain tumors as a complementary system to traditional transgenic animal and cell line systems.
Collapse
Affiliation(s)
- Biren Dave
- Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Jignesh Tailor
- Division of Pediatric Neurosurgery, Riley Hospital for Children, Indianapolis, IN, USA.
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
| |
Collapse
|
|
8
|
Takemon Y, Pleasance ED, Gagliardi A, Hughes CS, Csizmok V, Wee K, Trinh DL, Huff RD, Mungall AJ, Moore RA, Chuah E, Mungall KL, Lewis E, Nelson J, Lim HJ, Renouf DJ, Jones SJ, Laskin J, Marra MA. Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities. Genome Med 2024; 16:136. [PMID: 39578878 PMCID: PMC11583415 DOI: 10.1186/s13073-024-01401-9] [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: 08/05/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required. METHODS Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function (KMT2DLOF) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes. RESULTS We revealed genetic interactors with functions in histone modification, metabolism, and immune response and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Notably, we predicted WRN as a novel SL interactor and, using recently available WRN inhibitor (HRO761 and VVD-133214) treatment response data, we observed that KMT2D mutational status significantly distinguishes treatment-sensitive MSI cell lines from treatment-insensitive MSI cell lines. CONCLUSIONS Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.
Collapse
Affiliation(s)
- Yuka Takemon
- Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, Canada
- Michael Smith Laboratories, University of British Columbia, Vancouver, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Erin D Pleasance
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Alessia Gagliardi
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | | | - Veronika Csizmok
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Kathleen Wee
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Diane L Trinh
- Michael Smith Laboratories, University of British Columbia, Vancouver, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Ryan D Huff
- Division of Respiratory Medicine, Department of Medicine, Air Pollution Exposure Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Andrew J Mungall
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Richard A Moore
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Eric Chuah
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Karen L Mungall
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Eleanor Lewis
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Jessica Nelson
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
| | - Howard J Lim
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | - Daniel J Renouf
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
- Pancreas Centre BC, Vancouver, BC, Canada
| | - Steven Jm Jones
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
| | - Janessa Laskin
- Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | - Marco A Marra
- Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, Canada.
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
| |
Collapse
|
|
9
|
Abu Sailik F, Emerald BS, Ansari SA. Opening and changing: mammalian SWI/SNF complexes in organ development and carcinogenesis. Open Biol 2024; 14:240039. [PMID: 39471843 PMCID: PMC11521604 DOI: 10.1098/rsob.240039] [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: 02/19/2024] [Revised: 07/04/2024] [Accepted: 09/18/2024] [Indexed: 11/01/2024] Open
Abstract
The switch/sucrose non-fermentable (SWI/SNF) subfamily are evolutionarily conserved, ATP-dependent chromatin-remodelling complexes that alter nucleosome position and regulate a spectrum of nuclear processes, including gene expression, DNA replication, DNA damage repair, genome stability and tumour suppression. These complexes, through their ATP-dependent chromatin remodelling, contribute to the dynamic regulation of genetic information and the maintenance of cellular processes essential for normal cellular function and overall genomic integrity. Mutations in SWI/SNF subunits are detected in 25% of human malignancies, indicating that efficient functioning of this complex is required to prevent tumourigenesis in diverse tissues. During development, SWI/SNF subunits help establish and maintain gene expression patterns essential for proper cellular identity and function, including maintenance of lineage-specific enhancers. Moreover, specific molecular signatures associated with SWI/SNF mutations, including disruption of SWI/SNF activity at enhancers, evasion of G0 cell cycle arrest, induction of cellular plasticity through pro-oncogene activation and Polycomb group (PcG) complex antagonism, are linked to the initiation and progression of carcinogenesis. Here, we review the molecular insights into the aetiology of human malignancies driven by disruption of the SWI/SNF complex and correlate these mechanisms to their developmental functions. Finally, we discuss the therapeutic potential of targeting SWI/SNF subunits in cancer.
Collapse
Affiliation(s)
- Fadia Abu Sailik
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- ASPIRE Precision Medicine Research Institute Abu Dhabi (PMRI-AD), United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| | - Suraiya Anjum Ansari
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, UAE
- ASPIRE Precision Medicine Research Institute Abu Dhabi (PMRI-AD), United Arab Emirates University, Al Ain, Abu Dhabi, UAE
| |
Collapse
|
|
10
|
LaRue-Nolan KC, Arul GLR, Sigafoos AN, Shi J, Fernandez-Zapico ME. Insights into the mechanisms driven by H3K4 KMTs in pancreatic cancer. Biochem J 2024; 481:983-997. [PMID: 39078225 PMCID: PMC11332384 DOI: 10.1042/bcj20230374] [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: 02/12/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/31/2024]
Abstract
Pancreatic cancer is a malignancy arising from the endocrine or exocrine compartment of this organ. Tumors from exocrine origin comprise over 90% of all pancreatic cancers diagnosed. Of these, pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype. The five-year survival rate for PDAC ranged between 5 and 9% for over four decades, and only recently saw a modest increase to ∼12-13%, making this a severe and lethal disease. Like other cancers, PDAC initiation stems from genetic changes. However, therapeutic targeting of PDAC genetic drivers has remained relatively unsuccessful, thus the focus in recent years has expanded to the non-genetic factors underlying the disease pathogenesis. Specifically, it has been proposed that dynamic changes in the epigenetic landscape promote tumor growth and metastasis. Emphasis has been given to the re-organization of enhancers, essential regulatory elements controlling oncogenic gene expression, commonly marked my histone 3 lysine 4 monomethylation (H3K4me1). H3K4me1 is typically deposited by histone lysine methyltransferases (KMTs). While well characterized as oncogenes in other cancer types, recent work has expanded the role of KMTs as tumor suppressor in pancreatic cancer. Here, we review the role and translational significance for PDAC development and therapeutics of KMTs.
Collapse
Affiliation(s)
- Kayla C. LaRue-Nolan
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, U.S.A
| | | | - Ashley N. Sigafoos
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A
| | - Jiaqi Shi
- Department of Pathology and Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, U.S.A
| | | |
Collapse
|
|
11
|
Jiao Y, Lv Y, Liu M, Liu Y, Han M, Xiong X, Zhou H, Zhong J, Kang X, Su W. The modification role and tumor association with a methyltransferase: KMT2C. Front Immunol 2024; 15:1444923. [PMID: 39165358 PMCID: PMC11333232 DOI: 10.3389/fimmu.2024.1444923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 07/22/2024] [Indexed: 08/22/2024] Open
Abstract
Histone methylation can affect chromosome structure and binding to other proteins, depending on the type of amino acid being modified and the number of methyl groups added, this modification may promote transcription of genes (H3K4me2, H3K4me3, and H3K79me3) or reduce transcription of genes (H3K9me2, H3K9me3, H3K27me2, H3K27me3, and H4K20me3). In addition, advances in tumor immunotherapy have shown that histone methylation as a type of protein post-translational modification is also involved in the proliferation, activation and metabolic reprogramming of immune cells in the tumor microenvironment. These post-translational modifications of proteins play a crucial role in regulating immune escape from tumors and immunotherapy. Lysine methyltransferases are important components of the post-translational histone methylation modification pathway. Lysine methyltransferase 2C (KMT2C), also known as MLL3, is a member of the lysine methyltransferase family, which mediates the methylation modification of histone 3 lysine 4 (H3K4), participates in the methylation of many histone proteins, and regulates a number of signaling pathways such as EMT, p53, Myc, DNA damage repair and other pathways. Studies of KMT2C have found that it is aberrantly expressed in many diseases, mainly tumors and hematological disorders. It can also inhibit the onset and progression of these diseases. Therefore, KMT2C may serve as a promising target for tumor immunotherapy for certain diseases. Here, we provide an overview of the structure of KMT2C, disease mechanisms, and diseases associated with KMT2C, and discuss related challenges.
Collapse
Affiliation(s)
- Yunjuan Jiao
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Yuanhao Lv
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Mingjie Liu
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yun Liu
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Miaomiao Han
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Xiwen Xiong
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Hongyan Zhou
- Xinxiang Key Laboratory of Precision Diagnosis and Treatment for Colorectal Cancer, Xinxiang First People’s Hospital, Xinxiang, China
| | - Jiateng Zhong
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
- Xinxiang Engineering Technology Research Center of Digestive Tumor Molecular Diagnosis, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Xiaohong Kang
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Wei Su
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Xinxiang Engineering Technology Research Center of Digestive Tumor Molecular Diagnosis, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| |
Collapse
|
|
12
|
Piffer S, Greto D, Ubaldi L, Mortilla M, Ciccarone A, Desideri I, Genitori L, Livi L, Marrazzo L, Pallotta S, Retico A, Sardi I, Talamonti C. Radiomic- and dosiomic-based clustering development for radio-induced neurotoxicity in pediatric medulloblastoma. Childs Nerv Syst 2024; 40:2301-2310. [PMID: 38642113 PMCID: PMC11269375 DOI: 10.1007/s00381-024-06416-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 04/15/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND Texture analysis extracts many quantitative image features, offering a valuable, cost-effective, and non-invasive approach for individual medicine. Furthermore, multimodal machine learning could have a large impact for precision medicine, as texture biomarkers can underlie tissue microstructure. This study aims to investigate imaging-based biomarkers of radio-induced neurotoxicity in pediatric patients with metastatic medulloblastoma, using radiomic and dosiomic analysis. METHODS This single-center study retrospectively enrolled children diagnosed with metastatic medulloblastoma (MB) and treated with hyperfractionated craniospinal irradiation (CSI). Histological confirmation of medulloblastoma and baseline follow-up magnetic resonance imaging (MRI) were mandatory. Treatment involved helical tomotherapy (HT) delivering a dose of 39 Gray (Gy) to brain and spinal axis and a posterior fossa boost up to 60 Gy. Clinical outcomes, such as local and distant brain control and neurotoxicity, were recorded. Radiomic and dosiomic features were extracted from tumor regions on T1, T2, FLAIR (fluid-attenuated inversion recovery) MRI-maps, and radiotherapy dose distribution. Different machine learning feature selection and reduction approaches were performed for supervised and unsupervised clustering. RESULTS Forty-eight metastatic medulloblastoma patients (29 males and 19 females) with a mean age of 12 ± 6 years were enrolled. For each patient, 332 features were extracted. Greater level of abstraction of input data by combining selection of most performing features and dimensionality reduction returns the best performance. The resulting one-component radiomic signature yielded an accuracy of 0.73 with sensitivity, specificity, and precision of 0.83, 0.64, and 0.68, respectively. CONCLUSIONS Machine learning radiomic-dosiomic approach effectively stratified pediatric medulloblastoma patients who experienced radio-induced neurotoxicity. Strategy needs further validation in external dataset for its potential clinical use in ab initio management paradigms of medulloblastoma.
Collapse
Affiliation(s)
- Stefano Piffer
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy.
| | - Daniela Greto
- Radiation Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Leonardo Ubaldi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| | - Marzia Mortilla
- Radiology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Antonio Ciccarone
- Medical Physics Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Isacco Desideri
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Lorenzo Genitori
- Neuro-Oncology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Lorenzo Livi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- Radiation Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Livia Marrazzo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| | - Stefania Pallotta
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| | | | - Iacopo Sardi
- Neuro-Oncology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Cinzia Talamonti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| |
Collapse
|
|
13
|
Wang T, Wang S, Wang T, Jia L, Nan G, Wang L. Cdc14B/Cyclin B1 signaling modulates the pathogenesis of sonic hedgehog subtype medulloblastoma. Am J Cancer Res 2024; 14:2868-2880. [PMID: 39005661 PMCID: PMC11236779 DOI: 10.62347/cvay8707] [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: 07/12/2023] [Accepted: 05/13/2024] [Indexed: 07/16/2024] Open
Abstract
Medulloblastoma (MB) is a severe malignancy of the central nervous system that predominantly occurs in the cerebellum of children. Overactivation of the sonic hedgehog (Shh) signaling pathway is the primary cause of the development and progression of Shh subtype MB, although the detailed mechanisms underlying this process remain largely elusive. In this study, we discovered that Shh can promote proliferation in MB cells through non-canonical Hedgehog signaling. This involves Shh binding to Patched 1, disrupting its interaction with Cyclin B1, allowing for nuclear translocation of Cyclin B1, and inducing the activation of genes involved in cell division. Furthermore, we observed that deregulation of Cdc14B leads to the stabilization of the Cyclin B1/CDK1 complex in MB cells through activating Cdc25C, a phosphatase known to help maintain Cyclin B1 stability. Our findings highlight the role of Cdc14B/Cdc25C/CDK1/Cyclin B1 in mediating Hedgehog signaling-driven pathogenesis in MB and have implications for identifying potential therapeutic targets.
Collapse
Affiliation(s)
- Ting Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityXi’an 710032, Shaanxi, China
| | - Shan Wang
- Institute of Basic Translational Medicine, Xi’an Medical UniversityXi’an 710021, Shaanxi, China
| | - Tao Wang
- The No. 2 Department of Neurology, Shaanxi Province People’s HospitalXi’an 710068, Shaanxi, China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityXi’an 710032, Shaanxi, China
| | - Gang Nan
- Department of Cell Biology, School of Basic Medical Sciences & National Translational Science Center for Molecular Medicine, Fourth Military Medical UniversityXi’an 710032, Shaanxi, China
| | - Liang Wang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical UniversityXi’an 710038, Shaanxi, China
| |
Collapse
|
|
14
|
Kubo N, Chen PB, Hu R, Ye Z, Sasaki H, Ren B. H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation. Mol Cell 2024; 84:1742-1752.e5. [PMID: 38513661 PMCID: PMC11069443 DOI: 10.1016/j.molcel.2024.02.030] [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: 12/24/2023] [Revised: 02/17/2024] [Accepted: 02/26/2024] [Indexed: 03/23/2024]
Abstract
Histone H3 lysine 4 mono-methylation (H3K4me1) marks poised or active enhancers. KMT2C (MLL3) and KMT2D (MLL4) catalyze H3K4me1, but their histone methyltransferase activities are largely dispensable for transcription during early embryogenesis in mammals. To better understand the role of H3K4me1 in enhancer function, we analyze dynamic enhancer-promoter (E-P) interactions and gene expression during neural differentiation of the mouse embryonic stem cells. We found that KMT2C/D catalytic activities were only required for H3K4me1 and E-P contacts at a subset of candidate enhancers, induced upon neural differentiation. By contrast, a majority of enhancers retained H3K4me1 in KMT2C/D catalytic mutant cells. Surprisingly, H3K4me1 signals at these KMT2C/D-independent sites were reduced after acute depletion of KMT2B, resulting in aggravated transcriptional defects. Our observations therefore implicate KMT2B in the catalysis of H3K4me1 at enhancers and provide additional support for an active role of H3K4me1 in enhancer-promoter interactions and transcription in mammalian cells.
Collapse
Affiliation(s)
- Naoki Kubo
- Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA; Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
| | - Poshen B Chen
- Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA; Genome Institute of Singapore, Agency for Science, Technology and Research (A(∗)STAR), Singapore, Singapore; Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, 7 Engineering Drive 1, Singapore 117574, Singapore
| | - Rong Hu
- Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Zhen Ye
- Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Hiroyuki Sasaki
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Bing Ren
- Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA; Center for Epigenomics, Department of Cellular and Molecular Medicine, Moores Cancer Center and Institute of Genome Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
| |
Collapse
|
|
15
|
Cao B, Sun C, Bi R, Liu Z, Jia Y, Cui W, Sun M, Yu B, Li X, Zhou X. Mutation landscape in Chinese nodal diffuse large B-cell lymphoma by targeted next generation sequencing and their relationship with clinicopathological characteristics. BMC Med Genomics 2024; 17:84. [PMID: 38609996 PMCID: PMC11015559 DOI: 10.1186/s12920-024-01866-y] [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: 07/22/2023] [Accepted: 04/05/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL), an aggressive and heterogenic malignant entity, is still a challenging clinical problem, since around one-third of patients are not cured with primary treatment. Next-generation sequencing (NGS) technologies have revealed common genetic mutations in DLBCL. We devised an NGS multi-gene panel to discover genetic features of Chinese nodal DLBCL patients and provide reference information for panel-based NGS detection in clinical laboratories. METHODS A panel of 116 DLBCL genes was designed based on the literature and related databases. We analyzed 96 Chinese nodal DLBCL biopsy specimens through targeted sequencing. RESULTS The most frequently mutated genes were KMT2D (30%), PIM1 (26%), SOCS1 (24%), MYD88 (21%), BTG1 (20%), HIST1H1E (18%), CD79B (18%), SPEN (17%), and KMT2C (16%). SPEN (17%) and DDX3X (6%) mutations were highly prevalent in our study than in Western studies. Thirty-three patients (34%) were assigned as genetic classification by the LymphGen algorithm, including 12 cases MCD, five BN2, seven EZB, seven ST2, and two EZB/ST2 complex. MYD88 L265P mutation, TP53 and BCL2 pathogenic mutations were unfavorable prognostic biomarkers in DLBCL. CONCLUSIONS This study presents the mutation landscape in Chinese nodal DLBCL, highlights the genetic heterogeneity of DLBCL and shows the role of panel-based NGS to prediction of prognosis and potential molecular targeted therapy in DLBCL. More precise genetic classification needs further investigations.
Collapse
Affiliation(s)
- Bing Cao
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
- Fudan University Medical Library, Shanghai, China
| | - Chenbo Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Rui Bi
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Zebing Liu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yijun Jia
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Wenli Cui
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Menghong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Baohua Yu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Xiaoqiu Li
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Institute of Pathology, Fudan University, Shanghai, China.
| |
Collapse
|
|
16
|
Tibben BM, Rothbart SB. Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation. J Mol Biol 2024; 436:168394. [PMID: 38092287 PMCID: PMC10957332 DOI: 10.1016/j.jmb.2023.168394] [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: 09/28/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023]
Abstract
DNA methylation is a well-studied epigenetic modification that has key roles in regulating gene expression, maintaining genome integrity, and determining cell fate. Precisely how DNA methylation patterns are established and maintained in specific cell types at key developmental stages is still being elucidated. However, research over the last two decades has contributed to our understanding of DNA methylation regulation by other epigenetic processes. Specifically, lysine methylation on key residues of histone proteins has been shown to contribute to the allosteric regulation of DNA methyltransferase (DNMT) activities. In this review, we discuss the dynamic interplay between DNA methylation and histone lysine methylation as epigenetic regulators of genome function by synthesizing key recent studies in the field. With a focus on DNMT3 enzymes, we discuss mechanisms of DNA methylation and histone lysine methylation crosstalk in the regulation of gene expression and the maintenance of genome integrity. Further, we discuss how alterations to the balance of various sites of histone lysine methylation and DNA methylation contribute to human developmental disorders and cancers. Finally, we provide perspectives on the current direction of the field and highlight areas for continued research and development.
Collapse
Affiliation(s)
- Bailey M Tibben
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Scott B Rothbart
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
| |
Collapse
|
|
17
|
Kang B, Xiao H, Ackley T, Shao L. Cancer Sample Analysis Utilizing Single-Nucleotide Polymorphism Array and Array Comparative Genomic Hybridization. Methods Mol Biol 2024; 2825:151-171. [PMID: 38913308 DOI: 10.1007/978-1-0716-3946-7_8] [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] [Indexed: 06/25/2024]
Abstract
Chromosomal microarray, including single-nucleotide polymorphism (SNP) array and array comparative genomic hybridization (aCGH), enables the detection of DNA copy-number loss and/or gain associated with unbalanced chromosomal aberrations. In addition, SNP array and aCGH with SNP component also detect copy-neutral loss of heterozygosity (CN-LOH). Here we describe the chromosomal microarray procedure from the sample preparation using extracted DNA to the scanning of the array chip.
Collapse
Affiliation(s)
- Benjamin Kang
- Department of Pathology and Pediatrics, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Hong Xiao
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Todd Ackley
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Lina Shao
- Department of Pathology and Pediatrics, University of Michigan, Ann Arbor, MI, USA.
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
|
18
|
Dhar SS, Brown C, Rizvi A, Reed L, Kotla S, Zod C, Abraham J, Abe JI, Rajaram V, Chen K, Lee M. Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.29.564587. [PMID: 37961118 PMCID: PMC10634931 DOI: 10.1101/2023.10.29.564587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and other types of cancer. Notably, heterozygous loss of KMT2D is prevalent in MB and other cancer types. However, what role heterozygous KMT2D loss plays in tumorigenesis has not been well characterized. Here, we show that heterozygous Kmt2d loss highly promotes MB driven by heterozygous loss of the MB suppressor gene Ptch in mice. Heterozygous Kmt2d loss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, in Ptch-mutant-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygous Kmt2d loss and upregulation of the oncogene MycN by heterozygous Ptch loss increased the expression of tumor-promoting genes. Moreover, heterozygous Kmt2d loss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g., Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygous Kmt2d loss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygous KMT2D loss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygous KMT2D loss.
Collapse
|
|
19
|
Buzova D, Frohlich J, Zapletalova D, Raffaele M, Lo Re O, Tsoneva DK, Sterba J, Cerveny J, Vinciguerra M. Detection of cell-free histones in the cerebrospinal fluid of pediatric central nervous system malignancies by imaging flow cytometry. Front Mol Biosci 2023; 10:1254699. [PMID: 38028540 PMCID: PMC10646437 DOI: 10.3389/fmolb.2023.1254699] [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: 07/07/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction: Pediatric brain tumours (PBT) are one of the most common malignancies during childhood, with variable severity according to the location and histological type. Certain types of gliomas, such a glioblastoma and diffuse intrinsic pontine glioma (DIPG), have a much higher mortality than ependymoma and medulloblastoma. Early detection of PBT is essential for diagnosis and therapeutic interventions. Liquid biopsies have been demonstrated using cerebrospinal fluid (CSF), mostly restricted to cell free DNA, which display limitations of quantity and integrity. In this pilot study, we sought to demonstrate the detectability and robustness of cell free histones in the CSF. Methods: We collected CSF samples from a pilot cohort of 8 children with brain tumours including DIPG, medulloblastoma, glioblastoma, ependymoma and others. As controls, we collected CSF samples from nine children with unrelated blood malignancies and without brain tumours. We applied a multichannel flow imaging approach on ImageStream(X) to image indiviual histone or histone complexes on different channels. Results: Single histones (H2A, macroH2A1.1, macroH2A1.2 H2B, H3, H4 and histone H3 bearing the H3K27M mutation), and histone complexes are specifically detectable in the CSF of PBT patients. H2A and its variants macroH2A1.1/macroH2A1/2 displayed the strongest signal and abundance, together with disease associated H3K27M. In contrast, mostly H4 is detectable in the CSF of pediatric patients with blood malignancies. Discussion: In conclusion, free histones and histone complexes are detectable with a strong signal in the CSF of children affected by brain tumours, using ImageStream(X) technology and may provide additive diagnostic and predictive information.
Collapse
Affiliation(s)
- Diana Buzova
- Department of Adaptive Biotechnologies, Global Change Research Institute CAS, Brno, Czechia
| | - Jan Frohlich
- International Clinical Research Center, St Anne’s University Hospital, Brno, Czechia
| | - Danica Zapletalova
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Marco Raffaele
- International Clinical Research Center, St Anne’s University Hospital, Brno, Czechia
| | - Oriana Lo Re
- International Clinical Research Center, St Anne’s University Hospital, Brno, Czechia
- Department of Stem Cell Biology and Transplantology, Research Institute of the Medical University of Varna, Varna, Bulgaria
| | - Desislava K. Tsoneva
- Department of Stem Cell Biology and Transplantology, Research Institute of the Medical University of Varna, Varna, Bulgaria
- Department of Medical Genetics, Medical University of Varna, Varna, Bulgaria
| | - Jaroslav Sterba
- International Clinical Research Center, St Anne’s University Hospital, Brno, Czechia
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Jan Cerveny
- Department of Adaptive Biotechnologies, Global Change Research Institute CAS, Brno, Czechia
| | - Manlio Vinciguerra
- International Clinical Research Center, St Anne’s University Hospital, Brno, Czechia
- Department of Stem Cell Biology and Transplantology, Research Institute of the Medical University of Varna, Varna, Bulgaria
- Faculty of Health, Liverpool John Moores University, Liverpool, United Kingdom
| |
Collapse
|
|
20
|
Sanghrajka RM, Koche R, Medrano H, El Nagar S, Stephen DN, Lao Z, Bayin NS, Ge K, Joyner AL. KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis. iScience 2023; 26:107831. [PMID: 37822508 PMCID: PMC10562805 DOI: 10.1016/j.isci.2023.107831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 03/29/2023] [Accepted: 09/01/2023] [Indexed: 10/13/2023] Open
Abstract
The major cause of treatment failure and mortality among medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in Sonic hedgehog-driven medulloblastoma (SHH-MB) patients, however, remain largely unknown. In this study we define a tumor suppressive role of KMT2D (MLL2), a gene frequently mutated in the most metastatic β-subtype. Strikingly, genetic mouse models of SHH-MB demonstrate that heterozygous loss of Kmt2d in conjunction with activation of the SHH pathway causes highly penetrant disease with decreased survival, increased hindbrain invasion and spinal cord metastasis. Loss of Kmt2d attenuates neural differentiation and shifts the transcriptional/chromatin landscape of primary and metastatic tumors toward a decrease in differentiation genes and tumor suppressors and an increase in genes/pathways implicated in advanced stage cancer and metastasis (TGFβ, Notch, Atoh1, Sox2, and Myc). Thus, secondary heterozygous KMT2D mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis.
Collapse
Affiliation(s)
- Reeti Mayur Sanghrajka
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Richard Koche
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hector Medrano
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Salsabiel El Nagar
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Daniel N. Stephen
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zhimin Lao
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - N. Sumru Bayin
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kai Ge
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Alexandra L. Joyner
- Developmental Biology Program, Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| |
Collapse
|
|
21
|
Caroleo AM, Rotulo S, Agolini E, Macchiaiolo M, Boccuto L, Antonelli M, Colafati GS, Cacchione A, Megaro G, Carai A, De Ioris MA, Lodi M, Tornesello A, Simone V, Torroni F, Cinalli G, Mastronuzzi A. SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome. Front Mol Neurosci 2023; 16:1228389. [PMID: 37692099 PMCID: PMC10483120 DOI: 10.3389/fnmol.2023.1228389] [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: 05/24/2023] [Accepted: 08/07/2023] [Indexed: 09/12/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.
Collapse
Affiliation(s)
- Anna Maria Caroleo
- Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| | - Silvia Rotulo
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Emanuele Agolini
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Marina Macchiaiolo
- Rare Diseases and Medical Genetics Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Luigi Boccuto
- School of Nursing, College of Behavioral, Social and Health Sciences Healthcare Genetics Interdisciplinary Doctoral Program, Clemson University, Clemson, SC, United States
| | - Manila Antonelli
- Faculty of Medicine and Dentistry, Department of Radiological, Oncological, and Pathological Anatomy Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Antonella Cacchione
- Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| | - Giacomina Megaro
- Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| | - Andrea Carai
- Neurosurgery Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| | - Maria Antonietta De Ioris
- Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| | - Mariachiara Lodi
- Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| | | | - Valeria Simone
- Pediatric Oncology Unit, Ospedale Vito Fazzi, Lecce, Italy
| | - Filippo Torroni
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Giuseppe Cinalli
- Pediatric Neurosurgery Unit, Department of Neuroscience, Santobono-Pausilipon Children’s Hospital, Naples, Italy
| | - Angela Mastronuzzi
- Department of Onco-Hematology, Cell Therapy, Gene Therapy and Hemopoietic Transplant, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
| |
Collapse
|
|
22
|
Slika H, Alimonti P, Raj D, Caraway C, Alomari S, Jackson EM, Tyler B. The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies. Cancers (Basel) 2023; 15:3889. [PMID: 37568705 PMCID: PMC10417410 DOI: 10.3390/cancers15153889] [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: 06/26/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with medulloblastoma remains dismal. Additionally, the high doses of radiation and the chemotherapeutic agents used are associated with significant short- and long-term complications and adverse effects, most notably neurocognitive delay. Hence, there is an urgent need for the development and clinical integration of targeted treatment regimens with greater efficacy and superior safety profiles. Since the adoption of the molecular-based classification of medulloblastoma into wingless (WNT) activated, sonic hedgehog (SHH) activated, group 3, and group 4, research efforts have been directed towards unraveling the genetic, epigenetic, transcriptomic, and proteomic profiles of each subtype. This review aims to delineate the progress that has been made in characterizing the neurodevelopmental and molecular features of each medulloblastoma subtype. It further delves into the implications that these characteristics have on the development of subgroup-specific targeted therapeutic agents. Furthermore, it highlights potential future avenues for combining multiple agents or strategies in order to obtain augmented effects and evade the development of treatment resistance in tumors.
Collapse
Affiliation(s)
- Hasan Slika
- Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon;
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.R.); (C.C.); (S.A.); (E.M.J.)
| | - Paolo Alimonti
- School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Divyaansh Raj
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.R.); (C.C.); (S.A.); (E.M.J.)
| | - Chad Caraway
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.R.); (C.C.); (S.A.); (E.M.J.)
| | - Safwan Alomari
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.R.); (C.C.); (S.A.); (E.M.J.)
| | - Eric M. Jackson
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.R.); (C.C.); (S.A.); (E.M.J.)
| | - Betty Tyler
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.R.); (C.C.); (S.A.); (E.M.J.)
| |
Collapse
|
|
23
|
Navickas SM, Giles KA, Brettingham-Moore KH, Taberlay PC. The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target. Oncogene 2023:10.1038/s41388-023-02773-9. [PMID: 37433987 PMCID: PMC10374441 DOI: 10.1038/s41388-023-02773-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 06/16/2023] [Accepted: 06/29/2023] [Indexed: 07/13/2023]
Abstract
The chromatin remodeler SMARCA4/BRG1 is a key epigenetic regulator with diverse roles in coordinating the molecular programs that underlie brain tumour development. BRG1 function in brain cancer is largely specific to the tumour type and varies further between tumour subtypes, highlighting its complexity. Altered SMARCA4 expression has been linked to medulloblastoma, low-grade gliomas such as oligodendroglioma, high-grade gliomas such as glioblastoma and atypical/teratoid rhabdoid tumours. SMARCA4 mutations in brain cancer predominantly occur in the crucial catalytic ATPase domain, which is associated with tumour suppressor activity. However, SMARCA4 is opposingly seen to promote tumourigenesis in the absence of mutation and through overexpression in other brain tumours. This review explores the multifaceted interaction between SMARCA4 and various brain cancer types, highlighting its roles in tumour pathogenesis, the pathways it regulates, and the advances that have been made in understanding the functional relevance of mutations. We discuss developments made in targeting SMARCA4 and the potential to translate these to adjuvant therapies able to enhance current methods of brain cancer treatment.
Collapse
Affiliation(s)
- Sophie M Navickas
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, 17 Liverpool Street, Hobart, TAS, 7000, Australia
| | - Katherine A Giles
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, 17 Liverpool Street, Hobart, TAS, 7000, Australia
- Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, NSW, 2145, Australia
| | - Kate H Brettingham-Moore
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, 17 Liverpool Street, Hobart, TAS, 7000, Australia
| | - Phillippa C Taberlay
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, 17 Liverpool Street, Hobart, TAS, 7000, Australia.
| |
Collapse
|
|
24
|
Zhao Z, Cao K, Watanabe J, Philips CN, Zeidner JM, Ishi Y, Wang Q, Gold SR, Junkins K, Bartom ET, Yue F, Chandel NS, Hashizume R, Ben-Sahra I, Shilatifard A. Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations. J Clin Invest 2023; 133:e169993. [PMID: 37252797 PMCID: PMC10313365 DOI: 10.1172/jci169993] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 05/09/2023] [Indexed: 06/01/2023] Open
Abstract
Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.
Collapse
Affiliation(s)
- Zibo Zhao
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Kaixiang Cao
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Jun Watanabe
- Department of Biochemistry and Molecular Genetics
- Robert H. Lurie NCI Comprehensive Cancer Center, and
| | - Cassandra N. Philips
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Jacob M. Zeidner
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Yukitomo Ishi
- Department of Biochemistry and Molecular Genetics
- Robert H. Lurie NCI Comprehensive Cancer Center, and
| | - Qixuan Wang
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Sarah R. Gold
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Katherine Junkins
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Elizabeth T. Bartom
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Feng Yue
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Navdeep S. Chandel
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
- Robert H. Lurie NCI Comprehensive Cancer Center, and
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Rintaro Hashizume
- Department of Biochemistry and Molecular Genetics
- Robert H. Lurie NCI Comprehensive Cancer Center, and
| | - Issam Ben-Sahra
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| | - Ali Shilatifard
- Department of Biochemistry and Molecular Genetics
- Simpson Querrey Center for Epigenetics
| |
Collapse
|
|
25
|
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.
Collapse
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
| |
Collapse
|
|
26
|
Manfreda L, Rampazzo E, Persano L. Wnt Signaling in Brain Tumors: A Challenging Therapeutic Target. BIOLOGY 2023; 12:biology12050729. [PMID: 37237541 DOI: 10.3390/biology12050729] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023]
Abstract
The involvement of Wnt signaling in normal tissue homeostasis and disease has been widely demonstrated over the last 20 years. In particular, dysregulation of Wnt pathway components has been suggested as a relevant hallmark of several neoplastic malignancies, playing a role in cancer onset, progression, and response to treatments. In this review, we summarize the current knowledge on the instructions provided by Wnt signaling during organogenesis and, particularly, brain development. Moreover, we recapitulate the most relevant mechanisms through which aberrant Wnt pathway activation may impact on brain tumorigenesis and brain tumor aggressiveness, with a particular focus on the mutual interdependency existing between Wnt signaling components and the brain tumor microenvironment. Finally, the latest anti-cancer therapeutic approaches employing the specific targeting of Wnt signaling are extensively reviewed and discussed. In conclusion, here we provide evidence that Wnt signaling, due to its pleiotropic involvement in several brain tumor features, may represent a relevant target in this context, although additional efforts will be needed to: (i) demonstrate the real clinical impact of Wnt inhibition in these tumors; (ii) overcome some still unsolved concerns about the potential systemic effects of such approaches; (iii) achieve efficient brain penetration.
Collapse
Affiliation(s)
- Lorenzo Manfreda
- Department of Women and Children's Health, University of Padova, Via Giustininani, 3, 35128 Padova, Italy
- Pediatric Research Institute, Corso Stati Uniti, 4, 35127 Padova, Italy
| | - Elena Rampazzo
- Department of Women and Children's Health, University of Padova, Via Giustininani, 3, 35128 Padova, Italy
- Pediatric Research Institute, Corso Stati Uniti, 4, 35127 Padova, Italy
| | - Luca Persano
- Department of Women and Children's Health, University of Padova, Via Giustininani, 3, 35128 Padova, Italy
- Pediatric Research Institute, Corso Stati Uniti, 4, 35127 Padova, Italy
| |
Collapse
|
|
27
|
Lin YT, Li CF, Wu HC, Jan YH, Kuo YH. Case report: Heterogenous SMARCA4-deficient thoracic non-small cell lung carcinoma with various responses to nivolumab. Front Immunol 2023; 14:1131448. [PMID: 37051241 PMCID: PMC10083322 DOI: 10.3389/fimmu.2023.1131448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 03/10/2023] [Indexed: 03/29/2023] Open
Abstract
SMARCA4-deficient non-small cell carcinoma is an aggressive neoplasm with poor outcome. Several studies have highlighted its immunochemistry, pathophysiology, and underlying mechanisms, but studies of its definite treatment are few. Here, we report on a 69-year-old male with heterogenous pathological presentations of SMARCA4-deficient non-small cell carcinoma. He initially presented with neck lymphadenopathies. Immunohistochemistry staining and genomic profiling confirmed the diagnosis of SMARCA4-deficient non-small cell carcinoma. The patient responded well to immune checkpoint inhibitors with nivolumab. However, new lesions with various pathological presentations and various responses to nivolumab appeared during the treatment course. The patient survived more than 3 years from the initial diagnosis. This case shows the efficacy of nivolumab to treat SMARCA4-deficient non-small cell lung carcinoma.
Collapse
Affiliation(s)
- Yun-Tzu Lin
- Department of Oncology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
- Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Hung-Chang Wu
- Department of Oncology, Chi-Mei Medical Center, Tainan, Taiwan
- College of Pharmacy and Science, Chia Nan University, Tainan, Taiwan
| | | | - Yu-Hsuan Kuo
- Department of Oncology, Chi-Mei Medical Center, Tainan, Taiwan
- College of Pharmacy and Science, Chia Nan University, Tainan, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| |
Collapse
|
|
28
|
Li Z, Zhao J, Tang Y. Advances in the role of SWI/SNF complexes in tumours. J Cell Mol Med 2023; 27:1023-1031. [PMID: 36883311 PMCID: PMC10098296 DOI: 10.1111/jcmm.17709] [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: 10/28/2022] [Revised: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
Cancer development is a complex process involving both genetic and epigenetic changes. The SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, one of the most studied ATP-dependent complexes, plays an important role in coordinating chromatin structural stability, gene expression and post-translational modifications. The SWI/SNF complex can be classified into BAF, PBAF and GBAF according to their constituent subunits. Cancer genome sequencing studies have shown a high incidence of mutations in genes encoding subunits of the SWI/SNF chromatin remodelling complex, with abnormalities in one or more of these genes present in nearly 25% of all cancers, which indicating that stabilizing normal expression of genes encoding subunits in the SWI/SNF complex may prevent tumorigenesis. In this paper, we will review the relationship between the SWI/SNF complex and some clinical tumours and its mechanism of action. The aim is to provide a theoretical basis to guide the diagnosis and treatment of tumours caused by mutations or inactivation of one or more genes encoding subunits of the SWI/SNF complex in the clinical setting.
Collapse
Affiliation(s)
- Ziwei Li
- Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jiumei Zhao
- Chongqing Nanchuan District People's Hospital, Chongqing, China
| | - Yu Tang
- The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China.,Department of Genetics, Zunyi Medical University, Guizhou, China
| |
Collapse
|
|
29
|
Namitz KEW, Tan S, Cosgrove MS. Hierarchical assembly of the MLL1 core complex regulates H3K4 methylation and is dependent on temperature and component concentration. J Biol Chem 2023; 299:102874. [PMID: 36623730 PMCID: PMC9939731 DOI: 10.1016/j.jbc.2023.102874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/30/2022] [Accepted: 12/31/2022] [Indexed: 01/09/2023] Open
Abstract
Enzymes of the mixed lineage leukemia (MLL) family of histone H3 lysine 4 (H3K4) methyltransferases are critical for cellular differentiation and development and are regulated by interaction with a conserved subcomplex consisting of WDR5, RbBP5, Ash2L, and DPY30. While pairwise interactions between complex subunits have been determined, the mechanisms regulating holocomplex assembly are unknown. In this investigation, we systematically characterized the biophysical properties of a reconstituted human MLL1 core complex and found that the MLL1-WDR5 heterodimer interacts with the RbBP5-Ash2L-DPY30 subcomplex in a hierarchical assembly pathway that is highly dependent on concentration and temperature. Surprisingly, we found that the disassembled state is favored at physiological temperature, where the enzyme rapidly becomes irreversibly inactivated, likely because of complex components becoming trapped in nonproductive conformations. Increased protein concentration partially overcomes this thermodynamic barrier for complex assembly, suggesting a potential regulatory mechanism for spatiotemporal control of H3K4 methylation. Together, these results are consistent with the hypothesis that regulated assembly of the MLL1 core complex underlies an important mechanism for establishing different H3K4 methylation states in mammalian genomes.
Collapse
Affiliation(s)
- Kevin E W Namitz
- State University of New York (SUNY) Upstate Medical University, Department of Biochemistry and Molecular Biology, Syracuse, NY, USA
| | - Song Tan
- Penn State University, Department of Biochemistry and Molecular Biology, University Park, PA, USA
| | - Michael S Cosgrove
- State University of New York (SUNY) Upstate Medical University, Department of Biochemistry and Molecular Biology, Syracuse, NY, USA.
| |
Collapse
|
|
30
|
Skitchenko R, Dinikina Y, Smirnov S, Krapivin M, Smirnova A, Morgacheva D, Artomov M. Case report: Somatic mutations in microtubule dynamics-associated genes in patients with WNT-medulloblastoma tumors. Front Oncol 2023; 12:1085947. [PMID: 36713498 PMCID: PMC9877404 DOI: 10.3389/fonc.2022.1085947] [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: 10/31/2022] [Accepted: 12/07/2022] [Indexed: 01/14/2023] Open
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor which accounts for about 20% of all pediatric brain tumors and 63% of intracranial embryonal tumors. MB is considered to arise from precursor cell populations present during an early brain development. Most cases (~70%) of MB occur at the age of 1-4 and 5-9, but are also infrequently found in adults. Total annual frequency of pediatric tumors is about 5 cases per 1 million children. WNT-subtype of MB is characterized by a high probability of remission, with a long-term survival rate of about 90%. However, in some rare cases there may be increased metastatic activity, which dramatically reduces the likelihood of a favorable outcome. Here we report two cases of MB with a histological pattern consistent with desmoplastic/nodular (DP) and classic MB, and genetically classified as WNT-MB. Both cases showed putative causal somatic protein truncating mutations identified in microtubule-associated genes: ARID2, TUBB4A, and ANK3.
Collapse
Affiliation(s)
- Rostislav Skitchenko
- Almazov National Medical Research Centre, St. Petersburg, Russia,Computer Technologies Laboratory, ITMO University, St. Petersburg, Russia
| | - Yulia Dinikina
- Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Sergey Smirnov
- Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Mikhail Krapivin
- Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Anna Smirnova
- Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Daria Morgacheva
- Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Mykyta Artomov
- Almazov National Medical Research Centre, St. Petersburg, Russia,Computer Technologies Laboratory, ITMO University, St. Petersburg, Russia,The Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States,Department of Pediatrics, Ohio State University, Columbus, OH, United States,*Correspondence: Mykyta Artomov,
| |
Collapse
|
|
31
|
Tayari MM, Fang C, Ntziachristos P. Context-Dependent Functions of KDM6 Lysine Demethylases in Physiology and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1433:139-165. [PMID: 37751139 DOI: 10.1007/978-3-031-38176-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Histone lysine methylation is a major epigenetic modification that participates in several cellular processes including gene regulation and chromatin structure. This mark can go awry in disease contexts such as cancer. Two decades ago, the discovery of histone demethylase enzymes thirteen years ago sheds light on the complexity of the regulation of this mark. Here we address the roles of lysine demethylases JMJD3 and UTX in physiological and disease contexts. The two demethylases play pivotal roles in many developmental and disease contexts via regulation of di- and trimethylation of lysine 27 on histone H3 (H3K27me2/3) in repressing gene expression programs. JMJD3 and UTX participate in several biochemical settings including methyltransferase and chromatin remodeling complexes. They have histone demethylase-dependent and -independent activities and a variety of context-specific interacting factors. The structure, amounts, and function of the demethylases can be altered in disease due to genetic alterations or aberrant gene regulation. Therefore, academic and industrial initiatives have targeted these enzymes using a number of small molecule compounds in therapeutic approaches. In this chapter, we will touch upon inhibitor formulations, their properties, and current efforts to test them in preclinical contexts to optimize their therapeutic outcomes. Demethylase inhibitors are currently used in targeted therapeutic approaches that might be particularly effective when used in conjunction with systemic approaches such as chemotherapy.
Collapse
Affiliation(s)
- Mina Masoumeh Tayari
- Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Celestia Fang
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Panagiotis Ntziachristos
- Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Center for Medical Genetics, Ghent University, Medical Research Building 2 (MRB2), Entrance 38, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
- Center for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
| |
Collapse
|
|
32
|
Kameda-Smith MM, Zhu H, Luo EC, Suk Y, Xella A, Yee B, Chokshi C, Xing S, Tan F, Fox RG, Adile AA, Bakhshinyan D, Brown K, Gwynne WD, Subapanditha M, Miletic P, Picard D, Burns I, Moffat J, Paruch K, Fleming A, Hope K, Provias JP, Remke M, Lu Y, Reya T, Venugopal C, Reimand J, Wechsler-Reya RJ, Yeo GW, Singh SK. Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma. Nat Commun 2022; 13:7506. [PMID: 36473869 PMCID: PMC9726987 DOI: 10.1038/s41467-022-35118-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 11/18/2022] [Indexed: 12/12/2022] Open
Abstract
Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.
Collapse
Affiliation(s)
- Michelle M. Kameda-Smith
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON Canada
| | - Helen Zhu
- grid.419890.d0000 0004 0626 690XComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Canada ,grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, Toronto, Canada ,grid.231844.80000 0004 0474 0428University Health Network, Toronto, ON Canada ,grid.494618.6Vector Institute Toronto, Toronto, ON Canada
| | - En-Ching Luo
- grid.266100.30000 0001 2107 4242Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Stem Cell Program, University of California San Diego, La Jolla, CA USA ,grid.468218.10000 0004 5913 3393Sanford Consortium for Regenerative Medicine, La Jolla, CA USA
| | - Yujin Suk
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Michael G DeGroote School of Medicine, McMaster University, Hamilton, Canada
| | - Agata Xella
- grid.479509.60000 0001 0163 8573Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA USA
| | - Brian Yee
- grid.266100.30000 0001 2107 4242Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Stem Cell Program, University of California San Diego, La Jolla, CA USA ,grid.468218.10000 0004 5913 3393Sanford Consortium for Regenerative Medicine, La Jolla, CA USA
| | - Chirayu Chokshi
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - Sansi Xing
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - Frederick Tan
- grid.266100.30000 0001 2107 4242Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Stem Cell Program, University of California San Diego, La Jolla, CA USA ,grid.468218.10000 0004 5913 3393Sanford Consortium for Regenerative Medicine, La Jolla, CA USA
| | - Raymond G. Fox
- grid.266100.30000 0001 2107 4242Departments of Pharmacology and Medicine, University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La Jolla, CA USA
| | - Ashley A. Adile
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - David Bakhshinyan
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - Kevin Brown
- grid.17063.330000 0001 2157 2938Donnelly Centre, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - William D. Gwynne
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - Minomi Subapanditha
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada
| | - Petar Miletic
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - Daniel Picard
- grid.14778.3d0000 0000 8922 7789Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ian Burns
- grid.25073.330000 0004 1936 8227Michael G DeGroote School of Medicine, McMaster University, Hamilton, Canada
| | - Jason Moffat
- grid.17063.330000 0001 2157 2938Donnelly Centre, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Kamil Paruch
- grid.10267.320000 0001 2194 0956Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic ,grid.483343.bInternational Clinical Research Center, St. Anne’s University Hospital in Brno, 602 00 Brno, Czech Republic
| | - Adam Fleming
- grid.25073.330000 0004 1936 8227McMaster University, Departments of Pediatrics, Hematology and Oncology Division, Hamilton, Canada
| | - Kristin Hope
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - John P. Provias
- grid.25073.330000 0004 1936 8227McMaster University, Departments of Neuropathology, Hamilton, Canada
| | - Marc Remke
- grid.14778.3d0000 0000 8922 7789Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Yu Lu
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada
| | - Tannishtha Reya
- grid.266100.30000 0001 2107 4242Departments of Pharmacology and Medicine, University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La Jolla, CA USA ,grid.239585.00000 0001 2285 2675Present Address: Herbert Irving Comprehensive Cancer Center, Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY USA
| | - Chitra Venugopal
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON Canada
| | - Jüri Reimand
- grid.419890.d0000 0004 0626 690XComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Canada ,grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, Toronto, Canada ,grid.17063.330000 0001 2157 2938Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Robert J. Wechsler-Reya
- grid.479509.60000 0001 0163 8573Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA USA ,grid.239585.00000 0001 2285 2675Present Address: Herbert Irving Comprehensive Cancer Center, Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY USA
| | - Gene W. Yeo
- grid.266100.30000 0001 2107 4242Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Stem Cell Program, University of California San Diego, La Jolla, CA USA ,grid.468218.10000 0004 5913 3393Sanford Consortium for Regenerative Medicine, La Jolla, CA USA
| | - Sheila K. Singh
- grid.25073.330000 0004 1936 8227Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON Canada ,grid.25073.330000 0004 1936 8227McMaster University, Department of Pediatrics, Hamilton, Canada
| |
Collapse
|
|
33
|
Deng H, Guo X, Feng N, Luo Y, Liu B, Liu S, Wu JI, Shi X. Targeting H3K27me3 demethylase to inhibit Shh signaling and cholesterol metabolism in medulloblastoma growth. Front Oncol 2022; 12:1057147. [DOI: 10.3389/fonc.2022.1057147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/21/2022] [Indexed: 12/02/2022] Open
Abstract
Previously we uncovered the epigenetic regulation of medulloblastoma that low levels of H3K27me3 are required for Shh target gene expression and medulloblastoma growth. Since Jmjd3, an H3K27me3 demethylase, is responsible for maintaining low H3K27me3 at Shh target genes, targeting Jmjd3 could be an efficient way to inhibit Shh signaling and medulloblastoma growth. Here we show that the small molecule GSK-J4, an inhibitor of Jmjd3, significantly inhibited the expression of Shh target genes in Shh responsive cell models and primary cerebellar granule neuron precursors. GSK-J4 also significantly reduced the growth of primary Shh medulloblastoma cultures. Treating human medulloblastoma cell line DaoY by GSK-J4 led to cell cycle arrest at G0/G1 phase with decreased cells in S-phase. Tumor cell proliferation was significantly inhibited by GSK-J4 treatment. Gene expression analyses showed that GSK-J4 additionally constrained the expression of key genes in cholesterol biosynthesis. Our results highlight the possibility that targeting H3K27me3 demethylase Jmjd3 with GSK-J4 to inhibit Shh signaling and cholesterol metabolism is a potential application to treat Shh medulloblastoma.
Collapse
|
|
34
|
Jiang J. Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol 2022; 85:107-122. [PMID: 33836254 PMCID: PMC8492792 DOI: 10.1016/j.semcancer.2021.04.003] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022]
Abstract
Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (GliR/CiR) to activator (GliA/CiA) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.
Collapse
Affiliation(s)
- Jin Jiang
- Department of Molecular Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
| |
Collapse
|
|
35
|
Unraveling the Role of the Tyrosine Tetrad from the Binding Site of the Epigenetic Writer MLL3 in the Catalytic Mechanism and Methylation Multiplicity. Int J Mol Sci 2022; 23:ijms231810339. [PMID: 36142254 PMCID: PMC9499395 DOI: 10.3390/ijms231810339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
MLL3, also known as KMT2C, is a lysine mono-methyltransferase in charge of the writing of an epigenetic mark on lysine 4 from histone 3. The catalytic site of MLL3 is composed of four tyrosines, namely, Y44, Y69, Y128, and Y130. Tyrosine residues are highly conserved among lysine methyltransferases’ catalytic sites, although their complete function is still unclear. The exploration of how modifications on these residues from the enzymatic machinery impact the enzymatic activity of MLL3 could shed light transversally into the inner functioning of enzymes with similar characteristics. Through the use of QMMM calculations, we focus on the effect of the mutation of each tyrosine from the catalytic site on the enzymatic activity and the product specificity in the current study. While we found that the mutations of Y44 and Y128 by phenylalanine inactivated the enzyme, the mutation of Y128 by alanine reactivated the enzymatic activity of MLL3. Moreover, according to our models, the Y128A mutant was even found to be capable of di- and tri-methylate lysine 4 from histone 3, what would represent a gain of function mutation, and could be responsible for the development of diseases. Finally, we were able to establish the inactivation mechanism, which involved the use of Y130 as a water occlusion structure, whose conformation, once perturbed by its mutation or Y128 mutant, allows the access of water molecules that sequester the electron pair from lysine 4 avoiding its methylation process and, thus, increasing the barrier height.
Collapse
|
|
36
|
Zhong S, Shengyu Liu, Xin Shi, Zhang X, Li K, Liu G, Li L, Tao S, Zheng B, Sheng W, Ye Z, Xing Q, Zhai Q, Ren L, Wu Y, Bao Y. Disulfiram in glioma: Literature review of drug repurposing. Front Pharmacol 2022; 13:933655. [PMID: 36091753 PMCID: PMC9448899 DOI: 10.3389/fphar.2022.933655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.
Collapse
|
|
37
|
Yi J, Kim B, Shi X, Zhan X, Lu QR, Xuan Z, Wu J. PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma. Cancer Res 2022; 82:2874-2886. [PMID: 35731926 PMCID: PMC9388591 DOI: 10.1158/0008-5472.can-21-4313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/29/2022] [Accepted: 06/15/2022] [Indexed: 11/16/2022]
Abstract
Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated sonic hedgehog (SHH) signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here, we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wild-type tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. Insulin-like growth factor 2 (IGF2) mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones. SIGNIFICANCE The identification of an oncogenic function of PRC2 heterogeneity in medulloblastoma provides insights into subclone competition and cooperation during heterogeneous tumor evolution.
Collapse
Affiliation(s)
- Jiaqing Yi
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - BongWoo Kim
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xuanming Shi
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiaoming Zhan
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Q. Richard Lu
- Brain Tumor Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Zhenyu Xuan
- Department of Biological Sciences, Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Jiang Wu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA,Correspondence: Jiang Wu, PhD, , Department of Physiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas TX 75390-9040, Phone: 214-648-1824
| |
Collapse
|
|
38
|
Zhang Y, He X, Gao H. KMT2C mutation in a Chinese man with primary multidrug-resistant metastatic adenocarcinoma of rete testis: a case report. BMC Urol 2022; 22:123. [PMID: 35945529 PMCID: PMC9361678 DOI: 10.1186/s12894-022-01075-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/26/2022] [Indexed: 11/19/2022] Open
Abstract
Background Adenocarcinoma of the rete testis (AORT) is an extremely rare malignant tumor with poor prognosis and limited responsiveness to traditional chemotherapy. Few previous studies have focused on the molecular mechanisms underlying therapy resistance in AORT and further scrutiny is required to enable searches for targeted drugs to guide treatment selection. Case presentation The current case concerns a 55-year-old man with AORT who presented with isolated bone metastasis at initial diagnosis and experienced rapid disease progression after multi-line platinum-based combination chemotherapy. Next-generation sequencing revealed a novel somatic lysine methyltransferase 2C (KMT2C) c.5605 T > C mutation in exon 36 with an abundance of 49.27%. The patient received antiangiogenic drug treatment for 2 months but this was discontinued due to unacceptable anorexia and nausea. He survived for 12 months after diagnosis. Conclusion A potential correlation between AORT primary multi-drug resistance and KMT2C mutations is implied. Further studies are needed to determine the efficacy of PARP1/2 inhibitors for tumors with KMT2C mutations.
Collapse
Affiliation(s)
- Yue Zhang
- Department of Oncology, General Hospital of Western Theatre Command, No. 270, Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, 610000, Sichuan, People's Republic of China
| | - Xiaoyan He
- Department of Pathology, General Hospital of Western Theatre Command, Chengdu, Sichuan, People's Republic of China
| | - Hui Gao
- Department of Oncology, General Hospital of Western Theatre Command, No. 270, Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, 610000, Sichuan, People's Republic of China.
| |
Collapse
|
|
39
|
Radiomics signature for the prediction of progression-free survival and radiotherapeutic benefits in pediatric medulloblastoma. Childs Nerv Syst 2022; 38:1085-1094. [PMID: 35394210 DOI: 10.1007/s00381-022-05507-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 03/18/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE To develop and validate a radiomics signature for progression-free survival (PFS) and radiotherapeutic benefits in pediatric medulloblastoma. MATERIALS AND METHODS We retrospectively enrolled 253 consecutive children with medulloblastoma from two hospitals. A total of 1294 radiomic features were extracted from the region of tumor on the T1-weighted and contrast-enhanced T1-weighted (CE-T1w) MRI. Radiomic feature selection and machine learning modelling were performed to build radiomics signature for the prediction of PFS on the training set. Moreover, the prognostic performance of the clinical parameters was investigated for PFS. The Concordance index (a value of 0.5 indicates no predictive discrimination, and a value of 1 indicates perfect predictive discrimination) was used to measure and compare the prognostic performance of these models. RESULTS The radiomics signature for the prediction of the PFS yielded Concordance indices of 0.711, 0.707, and 0.717 on the training and held-out test sets 1 and 2, respectively. The radiomics nomogram integrating the radiomics signature, age, and metastasis performed better than the nomogram incorporating only clinicopathological factors (C-index, 0.723 vs. 0.665 and 0.722 vs. 0.677 on the held-out test sets 1 and 2, respectively), which was also validated by the good calibration and decision curve analysis. Further analysis demonstrated that patients with lower value of radiomics signature were associated with better clinical outcomes after postoperative radiotherapy (p < 0.001). CONCLUSION The radiomics signature and nomogram performed well for the prediction of PFS and could stratify patients underwent postoperative radiotherapy into the high- and low-risk groups with significantly different clinical outcomes.
Collapse
|
|
40
|
Greuter L, Frank N, Guzman R, Soleman J. The Clinical Applications of Liquid Biopsies in Pediatric Brain Tumors: A Systematic Literature Review. Cancers (Basel) 2022; 14:cancers14112683. [PMID: 35681663 PMCID: PMC9179879 DOI: 10.3390/cancers14112683] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/03/2022] [Accepted: 05/25/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Brain tumors are the most common solid cancer in children and are traditionally diagnosed via a tissue biopsy or resection. Liquid biopsy offers the possibility to characterize brain tumors based on their circulating DNA in blood, cerebrospinal fluid or even urine. Moreover, disease progress can be monitored accurately and sometimes even detected before radiographic progression. More trials are needed to standardize the use of liquid biopsy in pediatric brain tumors. Abstract Background: Pediatric brain tumors are the most common solid tumor in children. Traditionally, tumor diagnosis and molecular analysis were carried out on tumor tissue harvested either via biopsy or resection. However, liquid biopsy allows analysis of circulating tumor DNA in corporeal fluids such as cerebrospinal fluid or blood. Methods: We performed a systematic review in Pubmed and Embase regarding the role of liquid biopsy in pediatric brain tumors. Results: Nine studies with a total of 570 patients were included. The preferred corporeal fluid for analysis with a relatively high yield of ct-DNA was cerebrospinal fluid (CSF). For high-grade glioma, liquid biopsy can successfully characterize H3K27mutations and predict tumor progression before it is radiographically detected. Moreover, liquid biopsy has the potential to distinguish between pseudo-progression and actual progression. In medulloblastoma, ct-DNA in the CSF can be used as a surrogate marker of measurable residual disease and correlates with response to therapy and progression of the tumor up to three months before radiographic detection. Conclusion: Liquid biopsy is primarily useful in high-grade pediatric brain tumors such as diffuse midline glioma or medulloblastoma. Disease detection and monitoring is feasible for both tumor entities. More trials to standardize its use for pediatric brain tumors are necessary.
Collapse
Affiliation(s)
- Ladina Greuter
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.F.); (R.G.); (J.S.)
- Correspondence:
| | - Nicole Frank
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.F.); (R.G.); (J.S.)
| | - Raphael Guzman
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.F.); (R.G.); (J.S.)
- Department of Neurosurgery and Pediatric Neurosurgery, University Hospital of Basel and Children’s Hospital, 4056 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4056 Basel, Switzerland
| | - Jehuda Soleman
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.F.); (R.G.); (J.S.)
- Department of Neurosurgery and Pediatric Neurosurgery, University Hospital of Basel and Children’s Hospital, 4056 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4056 Basel, Switzerland
| |
Collapse
|
|
41
|
Eisemann T, Wechsler-Reya RJ. Coming in from the cold: overcoming the hostile immune microenvironment of medulloblastoma. Genes Dev 2022; 36:514-532. [PMID: 35680424 PMCID: PMC9186392 DOI: 10.1101/gad.349538.122] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Medulloblastoma is an aggressive brain tumor that occurs predominantly in children. Despite intensive therapy, many patients die of the disease, and novel therapies are desperately needed. Although immunotherapy has shown promise in many cancers, the low mutational burden, limited infiltration of immune effector cells, and immune-suppressive microenvironment of medulloblastoma have led to the assumption that it is unlikely to respond to immunotherapy. However, emerging evidence is challenging this view. Here we review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medulloblastoma patients and their families.
Collapse
Affiliation(s)
- Tanja Eisemann
- Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA
| | - Robert J Wechsler-Reya
- Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.,Department of Pediatrics, University of California at San Diego, La Jolla, California 92161, USA
| |
Collapse
|
|
42
|
Loss of ARID1A expression is associated with systemic inflammation markers and has important prognostic significance in gastric cancer. J Cancer Res Clin Oncol 2022; 148:1583-1595. [PMID: 35294647 DOI: 10.1007/s00432-022-03971-w] [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: 11/17/2021] [Accepted: 02/22/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND The tumor suppressor gene AT-rich interactive domain 1A (ARID1A) and systemic inflammatory response (SIR) have been reported to be related to the sensitivity to immunotherapy. This study intended to explore the relationship between ARID1A expression and SIR, and to further elucidate the prognostic value of ARID1A expression in gastric cancer (GC). METHODS The mRNA and protein expression of ARID1A were detected in 272 formalin-fixed paraffin-embedded (FFPE) tumor tissues. The data of nine systemic inflammation markers were collected 1 week before gastrectomy. Univariate and multivariate COX analysis were used to screen out independent predictors of GC. RESULTS Negative expression of ARID1A protein was related to GC with deficient mismatch repair (dMMR) (p = 0.033), positive programmed cell death-ligand 1 (PD-L1) (p = 0.005) and lower albumin level (p = 0.0064). Low expression of ARID1A mRNA was common in GC with abnormal E-cadherin (p = 0.020) and a higher platelet/lymphocyte ratio (PLR) (p = 0.0391). Multivariate COX analysis showed that the expression of ARID1A protein (p = 0.023), age (p = 0.004), T stage (p = 0.009) and N stage (p = 0.009) were independent predictors of GC. The nomogram established by independent predictors can accurately evaluate the survival risk of patients with GC. CONCLUSIONS The loss of ARID1A protein expression was associated with the dMMR subtype and high expression of PD-L1 in GC. Negative ARID1A protein and low expression of mRNA were associated with aberrant systemic inflammatory markers. The expression of ARID1A protein had important prognostic significance in GC.
Collapse
|
|
43
|
Bharathy N, Cleary MM, Kim JA, Nagamori K, Crawford KA, Wang E, Saha D, Settelmeyer TP, Purohit R, Skopelitis D, Chang K, Doran JA, Kirschbaum CW, Bharathy S, Crews DW, Randolph ME, Karnezis AN, Hudson-Price L, Dhawan J, Michalek JE, Ciulli A, Vakoc CR, Keller C. SMARCA4 biology in alveolar rhabdomyosarcoma. Oncogene 2022; 41:1647-1656. [PMID: 35094009 PMCID: PMC9985831 DOI: 10.1038/s41388-022-02205-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/21/2021] [Accepted: 01/20/2022] [Indexed: 11/09/2022]
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.
Collapse
Affiliation(s)
- Narendra Bharathy
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA,Present Address: Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA 19104 USA
| | - Megan M. Cleary
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | - Jin-Ah Kim
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | - Kiyo Nagamori
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | | | - Eric Wang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 USA
| | - Debarya Saha
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA,CSIR-CCMB, Uppal Road, Hyderabad 500007 India
| | | | - Reshma Purohit
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | | | - Kenneth Chang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 USA
| | - Jessica A. Doran
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | - C. Ward Kirschbaum
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | - Suriya Bharathy
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | - Davis W. Crews
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | | | - Anthony N. Karnezis
- University of California C Davis Medical Center, Sacramento, CA 95817 USA,British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3 Canada
| | - Lisa Hudson-Price
- Children’s Cancer Therapy Development Institute, Beaverton, OR 97005 USA
| | | | - Joel E. Michalek
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229 USA
| | - Alessio Ciulli
- Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
| | | | - Charles Keller
- Children's Cancer Therapy Development Institute, Beaverton, OR, 97005, USA.
| |
Collapse
|
|
44
|
Epigenetic mechanisms in paediatric brain tumours: regulators lose control. Biochem Soc Trans 2022; 50:167-185. [PMID: 35076654 DOI: 10.1042/bst20201227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/28/2021] [Accepted: 12/23/2021] [Indexed: 12/11/2022]
Abstract
Epigenetic mechanisms are essential to regulate gene expression during normal development. However, they are often disrupted in pathological conditions including tumours, where they contribute to their formation and maintenance through altered gene expression. In recent years, next generation genomic techniques has allowed a remarkable advancement of our knowledge of the genetic and molecular landscape of paediatric brain tumours and have highlighted epigenetic deregulation as a common hallmark in their pathogenesis. This review describes the main epigenetic dysregulations found in paediatric brain tumours, including at DNA methylation and histone modifications level, in the activity of chromatin-modifying enzymes and in the expression of non-coding RNAs. How these altered processes influence tumour biology and how they can be leveraged to dissect the molecular heterogeneity of these tumours and contribute to their classification is also addressed. Finally, the availability and value of preclinical models as well as the current clinical trials exploring targeting key epigenetic mediators in paediatric brain tumours are discussed.
Collapse
|
|
45
|
Qi L, Lindsay H, Kogiso M, Du Y, Braun FK, Zhang H, Guo L, Zhao S, Injac SG, Baxter PA, Su JM, Xiao S, Erickson SW, Earley EJ, Teicher B, Smith MA, Li XN. Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies. J Transl Med 2022; 102:185-193. [PMID: 34802040 PMCID: PMC10228180 DOI: 10.1038/s41374-021-00700-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/09/2022] Open
Abstract
Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.
Collapse
Affiliation(s)
- Lin Qi
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Pharmacology, School of Medicine, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Holly Lindsay
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Mari Kogiso
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Yuchen Du
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Frank K Braun
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Huiyuan Zhang
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Lei Guo
- Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA
| | - Sibo Zhao
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Sarah G Injac
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Patricia A Baxter
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Jack Mf Su
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Sophie Xiao
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | | | | | | | - Xiao-Nan Li
- Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| |
Collapse
|
|
46
|
Tsygankova S, Komova D, Boulygina E, Slobodova N, Sharko F, Rastorguev S, Gladysheva-Azgari M, Koroleva D, Smol’yaninova A, Tatarnikova S, Obuchova T, Nedoluzhko A, Gabeeva N, Zvonkov E. Non-GCB Diffuse Large B-Cell Lymphoma With an Atypical Disease Course: A Case Report and Clinical Exome Analysis. World J Oncol 2022; 13:38-47. [PMID: 35317330 PMCID: PMC8913013 DOI: 10.14740/wjon1436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/31/2021] [Indexed: 11/27/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid tumor among other non-Hodgkin lymphomas (30-40% of all cases). This type of lymphoma is characterized by significant differences in treatment response and the heterogeneity of clinical traits. Approximately 60% of patients are cured using standard chemotherapy (CT), while in 10-15% of cases, the tumor is characterized by an extremely aggressive course and resistance to even the most high-dose programs with autologous stem cell transplantation (auto-SCT). The activated B-cell (ABC) subtype of DLBCL is characterized by poor prognosis. Here, we describe a clinical case of diffuse ABC-DLBCL with an atypical disease course. Complete remission was achieved after four courses of CT, followed by autologous hematopoietic stem cell transplantation (auto-HSCT). However, early relapse occurred 2 months after the completion of treatment. According to the results of cytogenetic studies, significant chromosome breakdowns were observed. Exome sequencing allowed for the detection of several novel mutations that affect components of the NOTCH2 and NF-κB signaling pathways, a number of epigenetic regulators (KMT2D, CREBBP, EP300, ARID1A, MEF2B), as well as members of the immunoglobulin superfamily (CD58 and CD70). Whether these mutations were the result of therapy or were originally present in the lymphoid tumor remains unclear. Nevertheless, the introduction of genomic technologies into clinical practice is important for making a diagnosis and developing a DLBCL treatment regimen with the use of targeted drugs.
Collapse
Affiliation(s)
- Svetlana Tsygankova
- National Research Center “Kurchatov Institute”, 123182 Moscow, Russia
- These authors contributed equally
| | - Daria Komova
- National Research Center “Kurchatov Institute”, 123182 Moscow, Russia
- These authors contributed equally
| | - Eugenia Boulygina
- National Research Center “Kurchatov Institute”, 123182 Moscow, Russia
| | - Natalia Slobodova
- National Research Center “Kurchatov Institute”, 123182 Moscow, Russia
| | - Fedor Sharko
- National Research Center “Kurchatov Institute”, 123182 Moscow, Russia
| | - Sergey Rastorguev
- National Research Center “Kurchatov Institute”, 123182 Moscow, Russia
| | | | - Daria Koroleva
- National Medical Hematology Research Center, 125167 Moscow, Russia
| | | | | | - Tatiana Obuchova
- National Medical Hematology Research Center, 125167 Moscow, Russia
| | - Artem Nedoluzhko
- Moscow Healthcare Department, Mental-Health Clinic No. 1 Named After N.A. Alexeev, 115191 Moscow, Russia
| | - Nelli Gabeeva
- National Medical Hematology Research Center, 125167 Moscow, Russia
| | - Eugene Zvonkov
- National Medical Hematology Research Center, 125167 Moscow, Russia
| |
Collapse
|
|
47
|
Lim C, Dismuke T, Malawsky D, Ramsey JD, Hwang D, Godfrey VL, Kabanov AV, Gershon TR, Sokolsky-Papkov M. Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib. SCIENCE ADVANCES 2022; 8:eabl5838. [PMID: 35080986 PMCID: PMC8791615 DOI: 10.1126/sciadv.abl5838] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/24/2021] [Indexed: 05/03/2023]
Abstract
The therapeutic potential of CDK4/6 inhibitors for brain tumors has been limited by recurrence. To address recurrence, we tested a nanoparticle formulation of CDK4/6 inhibitor palbociclib (POx-Palbo) in mice genetically-engineered to develop SHH-driven medulloblastoma, alone or in combination with specific agents suggested by our analysis. Nanoparticle encapsulation reduced palbociclib toxicity, enabled parenteral administration, improved CNS pharmacokinetics, and extended mouse survival, but recurrence persisted. scRNA-seq identified up-regulation of glutamate transporter Slc1a2 and down-regulation of diverse ribosomal genes in proliferating medulloblastoma cells in POx-Palbo-treated mice, suggesting mTORC1 signaling suppression, subsequently confirmed by decreased 4EBP1 phosphorylation. Combining POx-Palbo with the mTORC1 inhibitor sapanisertib produced mutually enhancing effects and prolonged mouse survival compared to either agent alone, contrasting markedly with other tested drug combinations. Our data show the potential of nanoparticle formulation and scRNA-seq analysis of resistance to improve brain tumor treatment and identify POx-Palbo + Sapanisertib as effective combinatorial therapy for SHH medulloblastoma.
Collapse
Affiliation(s)
- Chaemin Lim
- Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Taylor Dismuke
- Department of Neurology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Pathology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Daniel Malawsky
- Department of Neurology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Jacob D. Ramsey
- Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Duhyeong Hwang
- Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Virginia L. Godfrey
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alexander V. Kabanov
- Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119992, Russia
| | - Timothy R. Gershon
- Department of Neurology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marina Sokolsky-Papkov
- Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
48
|
Yildiz CB, Zimmer-Bensch G. Role of DNMTs in the Brain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1389:363-394. [DOI: 10.1007/978-3-031-11454-0_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
49
|
Ray S, Chaturvedi NK, Bhakat KK, Rizzino A, Mahapatra S. Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment. Diagnostics (Basel) 2021; 12:diagnostics12010061. [PMID: 35054230 PMCID: PMC8774967 DOI: 10.3390/diagnostics12010061] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/11/2021] [Accepted: 12/18/2021] [Indexed: 12/24/2022] Open
Abstract
Medulloblastoma (MB) is the most common malignant central nervous system tumor in pediatric patients. Mainstay of therapy remains surgical resection followed by craniospinal radiation and chemotherapy, although limitations to this therapy are applied in the youngest patients. Clinically, tumors are divided into average and high-risk status on the basis of age, metastasis at diagnosis, and extent of surgical resection. However, technological advances in high-throughput screening have facilitated the analysis of large transcriptomic datasets that have been used to generate the current classification system, dividing patients into four primary subgroups, i.e., WNT (wingless), SHH (sonic hedgehog), and the non-SHH/WNT subgroups 3 and 4. Each subgroup can further be subdivided on the basis of a combination of cytogenetic and epigenetic events, some in distinct signaling pathways, that activate specific phenotypes impacting patient prognosis. Here, we delve deeper into the genetic basis for each subgroup by reviewing the extent of cytogenetic events in key genes that trigger neoplastic transformation or that exhibit oncogenic properties. Each of these discussions is further centered on how these genetic aberrations can be exploited to generate novel targeted therapeutics for each subgroup along with a discussion on challenges that are currently faced in generating said therapies. Our future hope is that through better understanding of subgroup-specific cytogenetic events, the field may improve diagnosis, prognosis, and treatment to improve overall quality of life for these patients.
Collapse
Affiliation(s)
- Sutapa Ray
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
| | - Nagendra K. Chaturvedi
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
| | - Kishor K. Bhakat
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Angie Rizzino
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sidharth Mahapatra
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Correspondence: ; Tel.: +1-(402)-599-7754
| |
Collapse
|
|
50
|
Fulciniti F, Barizzi J, Migliora P, Papadia A, Mazzucchelli L. Cytologic presentation of ovarian large cell carcinoma with rhabdoid features detected on peritoneal washing. Report of one case with cyto-histologic correlation and previously undescribed inactivating SMARCA-4 mutations. Diagn Cytopathol 2021; 50:E95-E99. [PMID: 34905290 DOI: 10.1002/dc.24908] [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: 10/11/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 11/11/2022]
Abstract
The SMARCA subgroup of genes belongs to the SWI1/SNF1 family, responsible for chromatin remodeling and repair within the nucleosome. The SMARCA4 gene is located on chromosome 19p13 and encodes the BRG1 (BRAhMA) protein. We report the cytological and histological findings in one case of large cell SMARCA4 deficient ovarian carcinoma with positive peritoneal washing in a 69-year-old woman. The neoplastic cells were present as singly lying or perivascular clusters and showed medium or large size, round to oval hyperchromatic nuclei, and scarce to moderate cytoplasms. Molecular pathology investigations performed on the ovarian surgical sample found two previously undescribed mutations in the SMARCA4 gene and additional mutations in the CTNNB1 (Beta Catenin gene) and in PIK3CA. To our knowledge, this case probably represents the third cytologic report of this variant of ovarian carcinoma and the first one with molecular pathologic study.
Collapse
Affiliation(s)
- Franco Fulciniti
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Jessica Barizzi
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Paola Migliora
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Andrea Papadia
- Servizio di Ginecologia e Ostetricia, Dipartimento di Ginecologia e Ostetricia, Ente Ospedaliero Cantonale, Ospedale Regionale di Lugano, Lugano, Switzerland
| | - Luca Mazzucchelli
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
| |
Collapse
|