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Villalard B, Boltjes A, Reynaud F, Imbaud O, Thoinet K, Timmerman I, Croze S, Theoulle E, Atzeni G, Lachuer J, Molenaar JJ, Tytgat GAM, Delloye-Bourgeois C, Castellani V. Neuroblastoma plasticity during metastatic progression stems from the dynamics of an early sympathetic transcriptomic trajectory. Nat Commun 2024; 15:9570. [PMID: 39500881 PMCID: PMC11538482 DOI: 10.1038/s41467-024-53776-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
Despite their indisputable importance in neuroblastoma (NB) pathology, knowledge of the bases of NB plasticity and heterogeneity remains incomplete. They may be rooted in developmental trajectories of their lineage of origin, the sympatho-adrenal neural crest. We find that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterize transcriptome states of NB cells and their dynamics over time and space, and compare them to those of fetal sympatho-adrenal tissues and patient tumors and bone marrow samples. Here we report remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian and patient datasets, we identify a list of genes upregulated during bone marrow involvement and associated with growth dependency, validating the relevance of our multimodal approach.
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Affiliation(s)
- Benjamin Villalard
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France
- Cancer Research Center of Lyon (CRCL), CNRS UMR5286, INSERM U1052, Université Claude Bernard Lyon 1 - 28 rue Laennec, F-69008, Lyon, France
| | - Arjan Boltjes
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Florie Reynaud
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France
- Cancer Research Center of Lyon (CRCL), CNRS UMR5286, INSERM U1052, Université Claude Bernard Lyon 1 - 28 rue Laennec, F-69008, Lyon, France
| | - Olivier Imbaud
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France
| | - Karine Thoinet
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France
| | - Ilse Timmerman
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Séverine Croze
- ProfileXpert, Claude Bernard Lyon 1 University, SFR santé LYON-EST, UCBL-INSERM US 7-CNRS UMS 3453, 69008, Lyon, France
| | - Emy Theoulle
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France
| | - Gianluigi Atzeni
- Cellenion SASU - Bioserra 2 - 60 avenue Rockefeller, F-69008, Lyon, France
| | - Joël Lachuer
- ProfileXpert, Claude Bernard Lyon 1 University, SFR santé LYON-EST, UCBL-INSERM US 7-CNRS UMS 3453, 69008, Lyon, France
- Cancer Research Center of Lyon (CRCL), CNRS UMR5286, INSERM U1052, Université Claude Bernard Lyon 1 - 28 rue Laennec, F-69008, Lyon, France
| | - Jan J Molenaar
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of pharmaceutical sciences. University of Utrecht, Utrecht, The Netherlands
| | - Godelieve A M Tytgat
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Division Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Céline Delloye-Bourgeois
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France.
- Cancer Research Center of Lyon (CRCL), CNRS UMR5286, INSERM U1052, Université Claude Bernard Lyon 1 - 28 rue Laennec, F-69008, Lyon, France.
| | - Valérie Castellani
- Université Claude Bernard Lyon 1, MeLis, CNRS UMR 5284, INSERM U1314, Faculté de Médecine et de Pharmacie - 8 avenue Rockefeller, F-69008, Lyon, France.
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Niebora J, Data K, Domagała D, Józkowiak M, Barrett S, Norizadeh Abbariki T, Bryja A, Kulus M, Woźniak S, Ziemak H, Piotrowska-Kempisty H, Antosik P, Bukowska D, Mozdziak P, Dzięgiel P, Kempisty B. Avian Models for Human Carcinogenesis-Recent Findings from Molecular and Clinical Research. Cells 2024; 13:1797. [PMID: 39513904 PMCID: PMC11544849 DOI: 10.3390/cells13211797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/24/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024] Open
Abstract
Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi's sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology.
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Affiliation(s)
- Julia Niebora
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
| | - Krzysztof Data
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
| | - Dominika Domagała
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
| | - Małgorzata Józkowiak
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
| | - Saoirse Barrett
- Human Clinical Embryology & Assisted Conception, School of Medicine, University of Dundee, Dundee DD1 4HN, UK
| | | | - Artur Bryja
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Sławomir Woźniak
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
| | - Hanna Ziemak
- Veterinary Clinic of the Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Science, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Bartosz Kempisty
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland (D.D.); (M.J.)
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
- Center of Assisted Reproduction, Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 601 77 Brno, Czech Republic
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3
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Huang Y, Fan M, Liu Y, Jiang X, Du K, Wu A, Li Q, Wu Y, Liang J, Wang K. Novel biomarkers and drug correlations of non-canonical WNT signaling in prostate and breast cancer. Discov Oncol 2024; 15:511. [PMID: 39347881 PMCID: PMC11442966 DOI: 10.1007/s12672-024-01394-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 09/24/2024] [Indexed: 10/01/2024] Open
Abstract
Prostate cancer (PCa) and breast cancer (BC) present formidable challenges in global cancer-related mortality, necessitating effective management strategies. The present study explores non-canonical Wnt signaling in PCa and BC, aiming to identify biomarkers and assess their clinical and therapeutic implications. Co-expression analyses reveal distinct gene patterns, with five overlapping genes (SULF1, ALG3, IL16, PLXNA2 and RASGFR2) exhibiting divergent expression in both cancers. Clinical relevance investigations demonstrate correlations with TNM stages and biochemical recurrence. Drug correlation analyses unveil potential therapeutic avenues, indicating that Wnt5a and ROR2 expressions are related to MEK inhibitor sensitivity in cancers. Meanwhile, further correlation analyses were conducted between drugs and the other novel non-canonical WNT genes (ALG3, IL16, SULF1, PLXNA2, and RASGRF2). Our findings contribute to understanding non-canonical Wnt signaling, offering insights into cancer progression and potential personalized treatment approaches.
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Affiliation(s)
- Yongming Huang
- Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Meiyin Fan
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yushuai Liu
- Ophthalmology Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaoying Jiang
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | | | | | - Qingyi Li
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yingying Wu
- Department of Mathematics, University of Houston, Houston, USA.
| | - Jiaqian Liang
- Department of Urology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Keshan Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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4
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Kibalnyk Y, Afanasiev E, Noble RMN, Watson AES, Poverennaya I, Dittmann NL, Alexiou M, Goodkey K, Greenwell AA, Ussher JR, Adameyko I, Massey J, Graf D, Bourque SL, Stratton JA, Voronova A. The chromatin regulator Ankrd11 controls cardiac neural crest cell-mediated outflow tract remodeling and heart function. Nat Commun 2024; 15:4632. [PMID: 38951500 PMCID: PMC11217281 DOI: 10.1038/s41467-024-48955-1] [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: 02/19/2023] [Accepted: 05/17/2024] [Indexed: 07/03/2024] Open
Abstract
ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-β in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function.
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Affiliation(s)
- Yana Kibalnyk
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
| | - Elia Afanasiev
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
| | - Ronan M N Noble
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
- Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2G3, Canada
| | - Adrianne E S Watson
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
| | - Irina Poverennaya
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, 1090, Vienna, Austria
| | - Nicole L Dittmann
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Neuroscience and Mental Health Institute, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Maria Alexiou
- Department of Dentistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Kara Goodkey
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
| | - Amanda A Greenwell
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
- Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Edmonton, AB, T6G 2H1, Canada
| | - John R Ussher
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
- Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Edmonton, AB, T6G 2H1, Canada
| | - Igor Adameyko
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, 1090, Vienna, Austria
- Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden
| | | | - Daniel Graf
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
- Department of Dentistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Stephane L Bourque
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada
- Department of Anesthesiology & Pain Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2G3, Canada
| | - Jo Anne Stratton
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
| | - Anastassia Voronova
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
- Women and Children's Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada.
- Neuroscience and Mental Health Institute, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
- Department of Cell Biology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
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Acloque H, Yang J, Theveneau E. Epithelial-to-mesenchymal plasticity from development to disease: An introduction to the special issue. Genesis 2024; 62:e23581. [PMID: 38098257 PMCID: PMC11021161 DOI: 10.1002/dvg.23581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 12/17/2023]
Abstract
Epithelial-Mesenchymal Transition (EMT) refers to the ability of cells to switch between epithelial and mesenchymal states, playing critical roles in embryonic development, wound healing, fibrosis, and cancer metastasis. Here, we discuss some examples that challenge the use of specific markers to define EMT, noting that their expression may not always correspond to the expected epithelial or mesenchymal identity. In concordance with recent development in the field, we emphasize the importance of generalizing the use of the term Epithelial-Mesenchymal Plasticity (EMP), to better capture the diverse and context-dependent nature of the bidirectional journey that cells can undertake between the E and M phenotypes. We highlight the usefulness of studying a wide range of physiological EMT scenarios, stress the value of the dynamic of expression of EMP regulators and advocate, whenever possible, for more systematic functional assays to assess cellular states.
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Affiliation(s)
- Hervé Acloque
- INRAE, AgroParisTech, GABI, Université Paris Saclay, Jouy en Josas, France
| | - Jing Yang
- Department of Pharmacology and of Pediatrics, Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, California, USA
| | - Eric Theveneau
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), CNRS, UPS, Université de Toulouse, Toulouse, France
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Zala M, Lipinski B, Costechareyre C, Jarrosson L, Teinturier R, Julia E, Lacourrège M, Verney A, Guitton J, Traverse-Glehen A, Bachy E, Salles G, Huet S, Genestier L, Castellani V, Delloye-Bourgeois C, Sujobert P. Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos. Leukemia 2024; 38:430-434. [PMID: 38225454 PMCID: PMC11514868 DOI: 10.1038/s41375-024-02150-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/02/2024] [Accepted: 01/09/2024] [Indexed: 01/17/2024]
Abstract
Despite achieving high rates of complete remission with RCHOP immuno-chemotherapy, almost all patients with follicular lymphoma (FL) will experience multiple relapses after treatment. The lack of experimental model of FL limits our understanding of heterogeneity in treatment response. Here we characterized a new model of FL patient-derived xenograft (PDX) in avian embryos. Based on 20 biopsies, we observed that tumor volume reduction upon RCHOP treatment in ovo predicted progression free survival in multivariate analysis. To further explore the model, we performed single-cell RNA sequencing and discovered a signature of 21 genes upregulated after RCHOP exposure, with significant intratumoral heterogeneity. Among these genes, we functionally validated BAX as a critical effector of RCHOP which can be targeted with venetoclax in vitro and in ovo . Overall, the FL-AVI-PDX model is a platform for functional precision oncology in FL, which captures both interpatient and intratumoral heterogeneity, and opens an avenue for drug development.
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Affiliation(s)
- Manon Zala
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
| | - Boris Lipinski
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
| | - Clélia Costechareyre
- OncoFactory, an ERBC company, Faculté de Médecine et de Pharmacie, 8 avenue Rockefeller, 69008, Lyon, France
| | - Loraine Jarrosson
- OncoFactory, an ERBC company, Faculté de Médecine et de Pharmacie, 8 avenue Rockefeller, 69008, Lyon, France
| | - Romain Teinturier
- OncoFactory, an ERBC company, Faculté de Médecine et de Pharmacie, 8 avenue Rockefeller, 69008, Lyon, France
| | - Edith Julia
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
| | - Marjorie Lacourrège
- OncoFactory, an ERBC company, Faculté de Médecine et de Pharmacie, 8 avenue Rockefeller, 69008, Lyon, France
| | - Aurélie Verney
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
| | - Jérôme Guitton
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service de biochimie, 69310, Pierre Bénite, France
| | - Alexandra Traverse-Glehen
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'Anatomopathologie, 69310, Pierre Bénite, France
| | - Emmanuel Bachy
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
| | - Gilles Salles
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sarah Huet
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'hématologie biologique, 69310, Pierre Bénite, France
| | - Laurent Genestier
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France
| | - Valérie Castellani
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France
| | - Céline Delloye-Bourgeois
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France
- Cancer Research Center of Lyon (CRCL, INSERM U1052-CNRS UMR5286, University of Lyon), University Claude Bernard Lyon 1, Centre Léon Bérard, 69008, Lyon, France
| | - Pierre Sujobert
- Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France.
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'hématologie biologique, 69310, Pierre Bénite, France.
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7
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Martínez-Pacheco ML, Hernández-Lemus E, Mejía C. Analysis of High-Risk Neuroblastoma Transcriptome Reveals Gene Co-Expression Signatures and Functional Features. BIOLOGY 2023; 12:1230. [PMID: 37759629 PMCID: PMC10525871 DOI: 10.3390/biology12091230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/01/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023]
Abstract
Neuroblastoma represents a neoplastic expansion of neural crest cells in the developing sympathetic nervous system and is childhood's most common extracranial solid tumor. The heterogeneity of gene expression in different types of cancer is well-documented, and genetic features of neuroblastoma have been described by classification, development stage, malignancy, and progression of tumors. Here, we aim to analyze RNA sequencing datasets, publicly available in the GDC data portal, of neuroblastoma tumor samples from various patients and compare them with normal adrenal gland tissue from the GTEx data portal to elucidate the gene expression profile and regulation networks they share. Our results from the differential expression, weighted correlation network, and functional enrichment analyses that we performed with the count data from neuroblastoma and standard normal gland samples indicate that the analysis of transcriptome data from 58 patients diagnosed with high-risk neuroblastoma shares the expression pattern of 104 genes. More importantly, our analyses identify the co-expression relationship and the role of these genes in multiple biological processes and signaling pathways strongly associated with this disease phenotype. Our approach proposes a group of genes and their biological functions to be further investigated as essential molecules and possible therapeutic targets of neuroblastoma regardless of the etiology of individual tumors.
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Affiliation(s)
| | | | - Carmen Mejía
- Faculty of Natural Sciences, Autonomous University of Queretaro, Queretaro 76010, Mexico;
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8
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Corallo D, Dalla Vecchia M, Lazic D, Taschner-Mandl S, Biffi A, Aveic S. The molecular basis of tumor metastasis and current approaches to decode targeted migration-promoting events in pediatric neuroblastoma. Biochem Pharmacol 2023; 215:115696. [PMID: 37481138 DOI: 10.1016/j.bcp.2023.115696] [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: 04/23/2023] [Revised: 07/12/2023] [Accepted: 07/12/2023] [Indexed: 07/24/2023]
Abstract
Cell motility is a crucial biological process that plays a critical role in the development of multicellular organisms and is essential for tissue formation and regeneration. However, uncontrolled cell motility can lead to the development of various diseases, including neoplasms. In this review, we discuss recent advances in the discovery of regulatory mechanisms underlying the metastatic spread of neuroblastoma, a solid pediatric tumor that originates in the embryonic migratory cells of the neural crest. The highly motile phenotype of metastatic neuroblastoma cells requires targeting of intracellular and extracellular processes, that, if affected, would be helpful for the treatment of high-risk patients with neuroblastoma, for whom current therapies remain inadequate. Development of new potentially migration-inhibiting compounds and standardized preclinical approaches for the selection of anti-metastatic drugs in neuroblastoma will also be discussed.
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Affiliation(s)
- Diana Corallo
- Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padova, Italy
| | - Marco Dalla Vecchia
- Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padova, Italy
| | - Daria Lazic
- St. Anna Children's Cancer Research Institute, CCRI, Zimmermannplatz 10, 1090, Vienna, Austria
| | - Sabine Taschner-Mandl
- St. Anna Children's Cancer Research Institute, CCRI, Zimmermannplatz 10, 1090, Vienna, Austria
| | - Alessandra Biffi
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Woman's and Child Health Department, University of Padova, 35121 Padova, Italy
| | - Sanja Aveic
- Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padova, Italy.
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9
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Goel A. Current understanding and future prospects on Berberine for anticancer therapy. Chem Biol Drug Des 2023; 102:177-200. [PMID: 36905314 DOI: 10.1111/cbdd.14231] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/11/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023]
Abstract
Berberine (BBR) is a potential plant metabolite and has remarkable anticancer properties. Many kinds of research are being focused on the cytotoxic activity of berberine in in vitro and in vivo studies. A variety of molecular targets which lead to the anticancer effect of berberine ranges from p-53 activation, Cyclin B expression for arresting cell cycles; protein kinase B (AKT), MAP kinase and IKB kinase for antiproliferative activity; effect on beclin-1 involved in autophagy; reduced expression of MMP-9 and MMP-2 for the inhibition of invasion and metastasis etc. Berberine also interferes with transcription factor-1 (AP-1) activity responsible for the expression of oncogenes and neoplastic transformation of the cell. It also leads to the inhibition of various enzymes which are directly or indirectly involved in carcinogenesis like N acetyl transferase, Cyclo-oxygenase-2, Telomerase and Topoisomerase. In addition to these actions, Berberine plays a role in, the regulation of reactive oxygen species and inflammatory cytokines in preventing cancer formation. Berberine anticancer properties are demonstrated due to the interaction of berberine with micro-RNA. The summarized information presented in this review article may help and lead the researchers, scientists/industry persons to use berberine as a promising candidate against cancer.
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Affiliation(s)
- Anjana Goel
- Department of Biotechnology, GLA University, Mathura, 281 46, Uttar Pradesh, India
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10
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Krawczyk E, Kitlińska J. Preclinical Models of Neuroblastoma-Current Status and Perspectives. Cancers (Basel) 2023; 15:3314. [PMID: 37444423 PMCID: PMC10340830 DOI: 10.3390/cancers15133314] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Preclinical in vitro and in vivo models remain indispensable tools in cancer research. These classic models, including two- and three-dimensional cell culture techniques and animal models, are crucial for basic and translational studies. However, each model has its own limitations and typically does not fully recapitulate the course of the human disease. Therefore, there is an urgent need for the development of novel, advanced systems that can allow for efficient evaluation of the mechanisms underlying cancer development and progression, more accurately reflect the disease pathophysiology and complexity, and effectively inform therapeutic decisions for patients. Preclinical models are especially important for rare cancers, such as neuroblastoma, where the availability of patient-derived specimens that could be used for potential therapy evaluation and screening is limited. Neuroblastoma modeling is further complicated by the disease heterogeneity. In this review, we present the current status of preclinical models for neuroblastoma research, discuss their development and characteristics emphasizing strengths and limitations, and describe the necessity of the development of novel, more advanced and clinically relevant approaches.
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Affiliation(s)
- Ewa Krawczyk
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Joanna Kitlińska
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
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11
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Fanlo L, Gómez-González S, Rozalén C, Pérez-Núñez I, Sangrador I, Tomás-Daza L, Gautier EL, Usieto S, Rebollo E, Vila-Ubach M, Carcaboso AM, Javierre BM, Celià-Terrassa T, Lavarino C, Martí E, Le Dréau G. Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting organotropic metastasis. Oncogene 2023:10.1038/s41388-023-02742-2. [PMID: 37301928 DOI: 10.1038/s41388-023-02742-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/16/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023]
Abstract
Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. Whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their neural crest, sympatho-adrenal origin remains unclear. Here, we identified the transcriptional signature distinguishing LR-NBs from HR-NBs, which consists mainly of genes that belong to the core sympatho-adrenal developmental program and are associated with favorable patient prognosis and with diminished disease progression. Gain- and loss-of-function experiments revealed that the top candidate gene of this signature, Neurexophilin-1 (NXPH1), has a dual impact on NB cell behavior in vivo: whereas NXPH1 and its receptor α-NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit organotropic colonization and metastasis. As suggested by RNA-seq analyses, these effects might result from the ability of NXPH1/α-NRXN signalling to restrain the conversion of NB cells from an adrenergic state to a mesenchymal one. Our findings thus uncover a transcriptional module of the sympatho-adrenal program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/α-NRXN signaling as a promising target to treat HR-NBs.
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Affiliation(s)
- Lucía Fanlo
- Department of Cells and Tissues, Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, C/ Baldiri Reixac 10-15, 08028, Barcelona, Spain
| | - Soledad Gómez-González
- SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Catalina Rozalén
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Iván Pérez-Núñez
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Irene Sangrador
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | | | - Emmanuel L Gautier
- Institut National de la Santé et de la Recherche Médicale (Inserm, UMR_S 1166), Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Susana Usieto
- Department of Cells and Tissues, Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, C/ Baldiri Reixac 10-15, 08028, Barcelona, Spain
| | - Elena Rebollo
- Molecular Imaging Platform, Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, C/ Baldiri Reixac 10-15, 08028, Barcelona, Spain
| | - Mònica Vila-Ubach
- SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Angel M Carcaboso
- SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Biola M Javierre
- Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Spain
| | - Toni Celià-Terrassa
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003, Barcelona, Spain
| | - Cinzia Lavarino
- SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Elisa Martí
- Department of Cells and Tissues, Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, C/ Baldiri Reixac 10-15, 08028, Barcelona, Spain
| | - Gwenvael Le Dréau
- Department of Cells and Tissues, Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, C/ Baldiri Reixac 10-15, 08028, Barcelona, Spain.
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.
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12
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Bhavsar SP. Metastasis in neuroblastoma: the MYCN question. Front Oncol 2023; 13:1196861. [PMID: 37274289 PMCID: PMC10233040 DOI: 10.3389/fonc.2023.1196861] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/08/2023] [Indexed: 06/06/2023] Open
Abstract
Oncogenic drivers like MYCN in neuroblastoma subsets continues to present a significant challenge owing to its strong correlation with high-risk metastatic disease and poor prognosis. However, only a limited number of MYCN-regulatory proteins associated with tumor initiation and progression have been elucidated. In this minireview, I summarize the recent progress in understanding the functional role of MYCN and its regulatory partners in neuroblastoma metastasis.
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13
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Jarrosson L, Dalle S, Costechareyre C, Tang Y, Grimont M, Plaschka M, Lacourrège M, Teinturier R, Le Bouar M, Maucort‐Boulch D, Eberhardt A, Castellani V, Caramel J, Delloye‐Bourgeois C. An in vivo avian model of human melanoma to perform rapid and robust preclinical studies. EMBO Mol Med 2023; 15:e16629. [PMID: 36692026 PMCID: PMC9994476 DOI: 10.15252/emmm.202216629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/20/2022] [Accepted: 12/23/2022] [Indexed: 01/25/2023] Open
Abstract
Metastatic melanoma patients carrying a BRAFV600 mutation can be treated with a combination of BRAF and MEK inhibitors (BRAFi/MEKi), but innate and acquired resistance invariably occurs. Predicting patient response to targeted therapies is crucial to guide clinical decision. We describe here the development of a highly efficient patient-derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI-PDXTM ). In this in vivo paradigm, we depict a fast and reproducible tumor engraftment of patient samples within the embryonic skin, preserving key molecular and phenotypic features. We show that sensitivity and resistance to BRAFi/MEKi can be reliably modeled in these AVI-PDXTM , as well as synergies with other drugs. We further provide proof-of-concept that the AVI-PDXTM models the diversity of responses of melanoma patients to BRAFi/MEKi, within days, hence positioning it as a valuable tool for the design of personalized medicine assays and for the evaluation of novel combination strategies.
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Affiliation(s)
| | - Stéphane Dalle
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of LyonLyonFrance
- Centre Hospitalier Lyon SudHospices Civils de LyonPierre BéniteFrance
| | | | - Yaqi Tang
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of LyonLyonFrance
| | - Maxime Grimont
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of LyonLyonFrance
| | - Maud Plaschka
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of LyonLyonFrance
| | | | | | - Myrtille Le Bouar
- Centre Hospitalier Lyon SudHospices Civils de LyonPierre BéniteFrance
| | | | - Anaïs Eberhardt
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of LyonLyonFrance
- Centre Hospitalier Lyon SudHospices Civils de LyonPierre BéniteFrance
| | - Valérie Castellani
- University of Lyon, University of Lyon 1 Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene InstituteLyonFrance
| | - Julie Caramel
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of LyonLyonFrance
| | - Céline Delloye‐Bourgeois
- University of Lyon, University of Lyon 1 Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene InstituteLyonFrance
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14
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Aaltonen K, Radke K, Adamska A, Seger A, Mañas A, Bexell D. Patient-derived models: Advanced tools for precision medicine in neuroblastoma. Front Oncol 2023; 12:1085270. [PMID: 36776363 PMCID: PMC9910084 DOI: 10.3389/fonc.2022.1085270] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/21/2022] [Indexed: 01/27/2023] Open
Abstract
Neuroblastoma is a childhood cancer derived from the sympathetic nervous system. High-risk neuroblastoma patients have a poor overall survival and account for ~15% of childhood cancer deaths. There is thus a need for clinically relevant and authentic models of neuroblastoma that closely resemble the human disease to further interrogate underlying mechanisms and to develop novel therapeutic strategies. Here we review recent developments in patient-derived neuroblastoma xenograft models and in vitro cultures. These models can be used to decipher mechanisms of metastasis and treatment resistance, for drug screening, and preclinical drug testing. Patient-derived neuroblastoma models may also provide useful information about clonal evolution, phenotypic plasticity, and cell states in relation to neuroblastoma progression. We summarize current opportunities for, but also barriers to, future model development and application. Integration of patient-derived models with patient data holds promise for the development of precision medicine treatment strategies for children with high-risk neuroblastoma.
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15
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Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E. GPC3-Unc5 receptor complex structure and role in cell migration. Cell 2022; 185:3931-3949.e26. [PMID: 36240740 PMCID: PMC9596381 DOI: 10.1016/j.cell.2022.09.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/22/2022] [Accepted: 09/15/2022] [Indexed: 11/09/2022]
Abstract
Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
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Affiliation(s)
- Onno Akkermans
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Céline Delloye-Bourgeois
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France
| | - Claudia Peregrina
- Department of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, Spain
| | - Maria Carrasquero-Ordaz
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Maria Kokolaki
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Miguel Berbeira-Santana
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Matthieu Chavent
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, Toulouse, France
| | - Florie Reynaud
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France
| | - Ritu Raj
- Department of Chemistry, University of Oxford, Oxford, UK
| | - Jon Agirre
- York Structural Biology Laboratory, Department of Chemistry, University of York, York, UK
| | - Metin Aksu
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Eleanor S White
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Edward Lowe
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Dounia Ben Amar
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France
| | - Sofia Zaballa
- Department of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, Spain
| | - Jiandong Huo
- Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus, Didcot, UK; Division of Structural Biology, University of Oxford, Oxford, UK
| | - Irene Pakos
- Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Patrick T N McCubbin
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Davide Comoletti
- Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA; School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
| | - Raymond J Owens
- Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus, Didcot, UK; Division of Structural Biology, University of Oxford, Oxford, UK
| | - Carol V Robinson
- Department of Chemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Valérie Castellani
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France.
| | - Daniel Del Toro
- Department of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, Spain.
| | - Elena Seiradake
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
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16
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Gonzalez Malagon SG, Liu KJ. Linking neural crest development to neuroblastoma pathology. Development 2022; 149:276149. [DOI: 10.1242/dev.200331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
Although rare, childhood (paediatric) cancers are a major cause of death in young children. Unlike many adult cancers, paediatric cancers, such as neuroblastoma (NB), are developmental diseases that rarely show genetic predispositions. NB is the most common extracranial solid tumour in children, accounting for ∼15% of paediatric cancer deaths. This heterogeneous cancer arises from undifferentiated neural crest-derived progenitor cells. As neural crest cells are multipotent and migratory, they are often considered the embryonic paradigm of cancer stem cells. However, very little is known about the events that trigger tumour initiation and progression. Here, we discuss recent insights into sympathoadrenal lineage specification, as well as genetic factors associated with NB. With this in mind, we consider the molecular underpinnings of NB in the context of developmental trajectories of the neural crest lineage. This allows us to compare distinct subtypes of the disease and gene-function interactions during sensitive phases of neural crest development.
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Affiliation(s)
- Sandra Guadalupe Gonzalez Malagon
- Biomedical Research Institute, Foundation for Research and Technology, University of Ioannina Campus 1 , 45115 Ioannina , Greece
- School of Health Sciences and Institute of Biosciences, University Research Centre, University of Ioannina 2 Department of Biological Applications and Technology , , 45110 Ioannina , Greece
| | - Karen J. Liu
- Centre for Craniofacial and Regenerative Biology, King's College London 3 , London SE1 9RT , UK
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17
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Gao F, Zhang G, Liu Y, He Y, Sheng Y, Sun X, Du Y, Yang C. Activation of CD44 signaling in leader cells induced by tumor-associated macrophages drives collective detachment in luminal breast carcinomas. Cell Death Dis 2022; 13:540. [PMID: 35680853 PMCID: PMC9184589 DOI: 10.1038/s41419-022-04986-4] [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: 02/04/2022] [Revised: 05/17/2022] [Accepted: 05/30/2022] [Indexed: 01/21/2023]
Abstract
Collective detachment of cancer cells at the invading front could generate efficient metastatic spread. However, how cancer cell clusters shed from the leading front remains unknown. We previously reported that the dynamic expression of CD44 in breast cancers (BrCas) at collectively invading edges was associated with tumor-associated macrophages (TAMs). In this study, we first observed that the highly expressed CD44 (CD44high) cancer cell clusters were located in the BrCa circulating vessels, accompanied by CD206+ TAMs. Next, we identified that the cancer cell clusters can be converted to an invasive CD44high state which was induced by TAMs, thus giving rise to CD44-associated signaling mediated cohesive detachment. Then, we showed that disrupting CD44-signaling inhibited the TAMs triggered cohesive detaching using 3D organotypic culture and mouse models. Furthermore, our mechanistic study showed that the acquisition of CD44high state was mediated by the MDM2/p53 pathway activation which was induced by CCL8 released from TAMs. Blocking of CCL8 could inhibit the signaling cascade which decreased the CD44-mediated cohesive detachment and spread. Our findings uncover a novel mechanism underlying collective metastasis in BrCas that may be helpful to seek for potential targets.
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Affiliation(s)
- Feng Gao
- grid.412528.80000 0004 1798 5117Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China ,grid.412528.80000 0004 1798 5117Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Guoliang Zhang
- grid.412528.80000 0004 1798 5117Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Yiwen Liu
- grid.412528.80000 0004 1798 5117Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Yiqing He
- grid.412528.80000 0004 1798 5117Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Yumeng Sheng
- grid.412528.80000 0004 1798 5117Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Xiaodan Sun
- grid.412528.80000 0004 1798 5117Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Yan Du
- grid.412528.80000 0004 1798 5117Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
| | - Cuixia Yang
- grid.412528.80000 0004 1798 5117Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China ,grid.412528.80000 0004 1798 5117Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233 China
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18
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Ben Amar D, Thoinet K, Villalard B, Imbaud O, Costechareyre C, Jarrosson L, Reynaud F, Novion Ducassou J, Couté Y, Brunet JF, Combaret V, Corradini N, Delloye-Bourgeois C, Castellani V. Environmental cues from neural crest derivatives act as metastatic triggers in an embryonic neuroblastoma model. Nat Commun 2022; 13:2549. [PMID: 35538114 PMCID: PMC9091272 DOI: 10.1038/s41467-022-30237-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Embryonic malignant transformation is concomitant to organogenesis, often affecting multipotent and migratory progenitors. While lineage relationships between malignant cells and their physiological counterparts are extensively investigated, the contribution of exogenous embryonic signals is not fully known. Neuroblastoma (NB) is a childhood malignancy of the peripheral nervous system arising from the embryonic trunk neural crest (NC) and characterized by heterogeneous and interconvertible tumor cell identities. Here, using experimental models mimicking the embryonic context coupled to proteomic and transcriptomic analyses, we show that signals released by embryonic sympathetic ganglia, including Olfactomedin-1, induce NB cells to shift from a noradrenergic to mesenchymal identity, and to activate a gene program promoting NB metastatic onset and dissemination. From this gene program, we extract a core signature specifically shared by metastatic cancers with NC origin. This reveals non-cell autonomous embryonic contributions regulating the plasticity of NB identities and setting pro-dissemination gene programs common to NC-derived cancers.
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Affiliation(s)
- Dounia Ben Amar
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller
| | - Karine Thoinet
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller
| | - Benjamin Villalard
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller
| | - Olivier Imbaud
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller
| | | | | | - Florie Reynaud
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller
| | - Julia Novion Ducassou
- University Grenoble Alpes, INSERM, CEA, UMR BioSanté U1292, CNRS, CEA, FR2048 38000, Grenoble, France
| | - Yohann Couté
- University Grenoble Alpes, INSERM, CEA, UMR BioSanté U1292, CNRS, CEA, FR2048 38000, Grenoble, France
| | - Jean-François Brunet
- Institut de Biologie de l'ENS (IBENS), Inserm, CNRS, École normale supérieure, PSL Research University, Paris, France
| | - Valérie Combaret
- Laboratory of Translational Research, Léon Bérard Centre, Lyon, France
| | - Nadège Corradini
- Departments of Oncology and Clinical Research, Centre Léon Berard and Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France
| | - Céline Delloye-Bourgeois
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller.
| | - Valérie Castellani
- University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France, 8 avenue Rockefeller.
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19
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Laut AK, Dorneburg C, Fürstberger A, Barth TFE, Kestler HA, Debatin KM, Beltinger C. CHD5 inhibits metastasis of neuroblastoma. Oncogene 2022; 41:622-633. [PMID: 34789839 PMCID: PMC8799470 DOI: 10.1038/s41388-021-02081-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 10/08/2021] [Accepted: 10/13/2021] [Indexed: 11/09/2022]
Abstract
CHD5, a tumor suppressor at 1p36, is frequently lost or silenced in poor prognosis neuroblastoma (NB) and many adult cancers. The role of CHD5 in metastasis is unknown. We confirm that low expression of CHD5 is associated with stage 4 NB. Forced expression of CHD5 in NB cell lines with 1p loss inhibited key aspects of the metastatic cascade in vitro: anchorage-independent growth, migration, and invasion. In vivo, formation of bone marrow and liver metastases developing from intravenously injected NB cells was delayed and decreased by forced CHD5 expression. Genome-wide mRNA sequencing revealed reduction of genes and gene sets associated with metastasis when CHD5 was overexpressed. Known metastasis-suppressing genes preferentially upregulated in CHD5-overexpressing NB cells included PLCL1. In patient NB, low expression of PLCL1was associated with metastatic disease and poor survival. Knockdown of PLCL1 and of p53 in IMR5 NB cells overexpressing CHD5 reversed CHD5-induced inhibition of invasion and migration in vitro. In summary, CHD5 is a metastasis suppressor in NB.
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Affiliation(s)
- Astrid K Laut
- Section Experimental Pediatric Oncology, Dept. of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Carmen Dorneburg
- Section Experimental Pediatric Oncology, Dept. of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Axel Fürstberger
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | | | - Hans A Kestler
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | - Klaus-Michael Debatin
- Dept. of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Christian Beltinger
- Section Experimental Pediatric Oncology, Dept. of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
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20
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An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers. iScience 2021; 24:103423. [PMID: 34849474 PMCID: PMC8608609 DOI: 10.1016/j.isci.2021.103423] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/30/2021] [Accepted: 11/08/2021] [Indexed: 11/26/2022] Open
Abstract
Lack of preclinical patient-derived xenograft cancer models in which to conduct large-scale molecular studies seriously impairs the development of effective personalized therapies. We report here an in vivo concept consisting of implanting human tumor cells in targeted tissues of an avian embryo, delivering therapeutics, evaluating their efficacy by measuring tumors using light sheet confocal microscopy, and conducting large-scale RNA-seq analysis to characterize therapeutic-induced changes in gene expression. The model was established to recapitulate triple-negative breast cancer (TNBC) and validated using TNBC standards of care and an investigational therapeutic agent.
Human TNBC cells implanted in the avian embryo survive and efficiently form tumors Anti-tumoral therapies intravenously injected are assessed by 3D imaging Post-graft large-scale analyses allow studying the mechanism of action of drugs The AVI-PDX allows preclinical evaluation of therapies and patient stratification
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21
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Tyumentseva A, Averchuk A, Palkina N, Zinchenko I, Moshev A, Savchenko A, Ruksha T. Transcriptomic Profiling Revealed Plexin A2 Downregulation With Migration and Invasion Alteration in Dacarbazine-Treated Primary Melanoma Cells. Front Oncol 2021; 11:732501. [PMID: 34926249 PMCID: PMC8677675 DOI: 10.3389/fonc.2021.732501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 11/16/2021] [Indexed: 12/02/2022] Open
Abstract
Melanoma is highly heterogeneous type of malignant neoplasm that is responsible for the majority of deaths among other types of skin cancer. In the present study, we screened a list of differentially expressed genes in two primary, drug-naïve melanoma cell lines derived from patients with melanoma following treatment of the cells with the chemotherapeutic agent dacarbazine. The aim was to determine the transcriptomic profiles and associated alterations in the cell phenotype. We found the vascular endothelial growth factor A/vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase/protein kinase B and focal adhesion signaling pathways to be top altered after dacarbazine treatment. In addition, we observed the expression levels of genes associated with tumor dissemination, integrin β8 and matrix metalloproteinase-1, to be diminished in both cell lines studied, the results of which were confirmed by reverse transcription-quantitative polymerase chain reaction. By contrast, plexin A2 expression was found to be upregulated in K2303 cells, where reduced migration and invasion were also observed, following dacarbazine treatment. Plexin A2 downregulation was associated with the promotion of migrative and invasive capacities in B0404 melanoma cells. Since plexin A2 is semaphorin co-receptor that is involved in focal adhesion and cell migration regulation, the present study suggested that plexin A2 may be implicated in the dacarbazine-mediated phenotypic shift of melanoma cells. We propose that the signature of cancer cell invasiveness can be revealed by using a combination of transcriptomic and functional approaches, which should be applied in the development of personalized therapeutic strategies for each patient with melanoma.
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Affiliation(s)
- Anna Tyumentseva
- Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia
- Federal Research Center Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia
| | - Anton Averchuk
- Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia
| | - Nadezhda Palkina
- Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia
| | - Ivan Zinchenko
- Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia
| | - Anton Moshev
- Laboratory of Cell Molecular Physiology and Pathology, Federal Research Center, Krasnoyarsk Science Center of The Siberian Branch of The Russian Academy of Sciences, Krasnoyarsk, Russia
| | - Andrey Savchenko
- Laboratory of Cell Molecular Physiology and Pathology, Federal Research Center, Krasnoyarsk Science Center of The Siberian Branch of The Russian Academy of Sciences, Krasnoyarsk, Russia
| | - Tatiana Ruksha
- Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia
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22
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Xue C, Li G, Lu J, Li L. Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther 2021; 6:400. [PMID: 34815385 PMCID: PMC8611092 DOI: 10.1038/s41392-021-00788-w] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs), covalently closed noncoding RNAs, are widely expressed in eukaryotes and viruses. They can function by regulating target gene expression, linear RNA transcription and protein generation. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays key roles in many biological and cellular processes, such as cell proliferation, growth, invasion, migration, and angiogenesis. It also plays a pivotal role in cancer progression. Emerging data suggest that the circRNA/PI3K/AKT axis modulates the expression of cancer-associated genes and thus regulates tumor progression. Aberrant regulation of the expression of circRNAs in the circRNA/PI3K/AKT axis is significantly associated with clinicopathological characteristics and plays an important role in the regulation of biological functions. In this review, we summarized the expression and biological functions of PI3K-AKT-related circRNAs in vitro and in vivo and assessed their associations with clinicopathological characteristics. We also further discussed the important role of circRNAs in the diagnosis, prognostication, and treatment of cancers.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Ganglei Li
- Department of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
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23
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Defining Pathological Activities of ALK in Neuroblastoma, a Neural Crest-Derived Cancer. Int J Mol Sci 2021; 22:ijms222111718. [PMID: 34769149 PMCID: PMC8584162 DOI: 10.3390/ijms222111718] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022] Open
Abstract
Neuroblastoma is a common extracranial solid tumour of childhood, responsible for 15% of cancer-related deaths in children. Prognoses vary from spontaneous remission to aggressive disease with extensive metastases, where treatment is challenging. Tumours are thought to arise from sympathoadrenal progenitor cells, which derive from an embryonic cell population called neural crest cells that give rise to diverse cell types, such as facial bone and cartilage, pigmented cells, and neurons. Tumours are found associated with mature derivatives of neural crest, such as the adrenal medulla or paraspinal ganglia. Sympathoadrenal progenitor cells express anaplastic lymphoma kinase (ALK), which encodes a tyrosine kinase receptor that is the most frequently mutated gene in neuroblastoma. Activating mutations in the kinase domain are common in both sporadic and familial cases. The oncogenic role of ALK has been extensively studied, but little is known about its physiological role. Recent studies have implicated ALK in neural crest migration and sympathetic neurogenesis. However, very few downstream targets of ALK have been identified. Here, we describe pathological activation of ALK in the neural crest, which promotes proliferation and migration, while preventing differentiation, thus inducing the onset of neuroblastoma. Understanding the effects of ALK activity on neural crest cells will help find new targets for neuroblastoma treatment.
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24
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Treffy RW, Rajan SG, Jiang X, Nacke LM, Malkana UA, Naiche LA, Bergey DE, Santana D, Rajagopalan V, Kitajewski JK, O'Bryan JP, Saxena A. Neuroblastoma differentiation in vivo excludes cranial tumors. Dev Cell 2021; 56:2752-2764.e6. [PMID: 34610330 PMCID: PMC10796072 DOI: 10.1016/j.devcel.2021.09.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/28/2021] [Accepted: 09/13/2021] [Indexed: 01/05/2023]
Abstract
Neuroblastoma (NB), the most common cancer in the first year of life, presents almost exclusively in the trunk. To understand why an early-onset cancer would have such a specific localization, we xenotransplanted human NB cells into discrete neural crest (NC) streams in zebrafish embryos. Here, we demonstrate that human NB cells remain in an undifferentiated, tumorigenic state when comigrating posteriorly with NC cells but, upon comigration into the head, differentiate into neurons and exhibit decreased survival. Furthermore, we demonstrate that this in vivo differentiation requires retinoic acid and brain-derived neurotrophic factor signaling from the microenvironment, as well as cell-autonomous intersectin-1-dependent phosphoinositide 3-kinase-mediated signaling, likely via Akt kinase activation. Our findings suggest a microenvironment-driven explanation for NB's trunk-biased localization and highlight the potential for induced differentiation to promote NB resolution in vivo.
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Affiliation(s)
- Randall W Treffy
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Sriivatsan G Rajan
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Xinghang Jiang
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Lynne M Nacke
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Usama A Malkana
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - L A Naiche
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Dani E Bergey
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Dianicha Santana
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Vinodh Rajagopalan
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Jan K Kitajewski
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - John P O'Bryan
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA; Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA
| | - Ankur Saxena
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
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25
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Xu W, Li S, Li M, Yang X, Xie S, Lin L, Li G, Zhou H. Targeted elimination of myeloid-derived suppressor cells via regulation of the STAT pathway alleviates tumor immunosuppression in neuroblastoma. Immunol Lett 2021; 240:31-40. [PMID: 34600949 DOI: 10.1016/j.imlet.2021.09.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/04/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023]
Abstract
Neuroblastoma (NB) has high morality rates and is the most common malignant tumor found in children. High aggregation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment results in immunosuppression and affects therapeutic effectiveness. At present, doxorubicin (DOX) and dopamine (DA) are the specific drugs used to selectively remove or mature MDSCs. The aim of the present study was to explore the feasibility and underlying mechanism of targeting elimination of MDSCs via DOX or DA administration to alleviate tumor immunosuppression in NB. In the present study, a BALB/c tumor-bearing mouse model was established, and mice were grouped into the control, DOX2.5, DOX5 and DA50 mg/kg groups. DOX or DA were injected intravenously on days 7 and 12 after inoculation, following which the parameters related to the signal transducer and activator of transcription (STAT) pathway in MDSCs, the proportion of MDSCs, T cell infiltration, programmed death-1 (PD-1) on the surface of T cells, the number of regulatory T cells (Tregs), polarization of tumor-related macrophages (TAMs) and tumor growth were compared between the groups on days 14, 17 and 23 after inoculation. The results demonstrated that following DOX or DA administration, STAT1/phosphorylated (p)-STAT1 decreased, whereas STAT3/p-STAT3, STAT5/p-STAT5 and STAT6/p-STAT6 increased, which was accompanied by a decrease in the MDSC proportion in each experimental group. Simultaneously, T cell infiltration in tumors was increased, whereas expression of PD-1, the number of Tregs, TAM polarization and tumor growth were inhibited. The most significant findings were observed in the DOX2.5 mg/kg group. To conclude, low dose DOX or DA administration could effectively regulate the STAT pathway to eliminate MDSCs, alleviate immunosuppression and improve the immune response against NB tumor cells.
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Affiliation(s)
- Weili Xu
- Departments of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China.
| | - Suolin Li
- Departments of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Meng Li
- Departments of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xiaofeng Yang
- Departments of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Shaojian Xie
- Departments of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Lin Lin
- Departments of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Guixin Li
- Departments of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Hui Zhou
- Departments of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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26
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Bedoya-Reina OC, Li W, Arceo M, Plescher M, Bullova P, Pui H, Kaucka M, Kharchenko P, Martinsson T, Holmberg J, Adameyko I, Deng Q, Larsson C, Juhlin CC, Kogner P, Schlisio S. Single-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors. Nat Commun 2021; 12:5309. [PMID: 34493726 PMCID: PMC8423786 DOI: 10.1038/s41467-021-24870-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 07/08/2021] [Indexed: 12/23/2022] Open
Abstract
Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.
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Affiliation(s)
- O C Bedoya-Reina
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
| | - W Li
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - M Arceo
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - M Plescher
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - P Bullova
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - H Pui
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - M Kaucka
- Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - P Kharchenko
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.,Harvard Stem Cell Institute, Cambridge, MA, USA
| | - T Martinsson
- Department of Pathology and Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - J Holmberg
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - I Adameyko
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Q Deng
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - C Larsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - C C Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - P Kogner
- Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - S Schlisio
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
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27
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Kasemeier-Kulesa JC, Spengler JA, Muolo CE, Morrison JA, Woolley TE, Schnell S, Kulesa PM. The embryonic trunk neural crest microenvironment regulates the plasticity and invasion of human neuroblastoma via TrkB signaling. Dev Biol 2021; 480:78-90. [PMID: 34416224 DOI: 10.1016/j.ydbio.2021.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 07/20/2021] [Accepted: 08/13/2021] [Indexed: 12/25/2022]
Abstract
Mistakes in trunk neural crest (NC) cell migration may lead to birth defects of the sympathetic nervous system (SNS) and neuroblastoma (NB) cancer. Receptor tyrosine kinase B (TrkB) and its ligand BDNF critically regulate NC cell migration during normal SNS development and elevated expression of TrkB is correlated with high-risk NB patients. However, in the absence of a model with in vivo interrogation of human NB cell and gene expression dynamics, the mechanistic role of TrkB in NB disease progression remains unclear. Here, we study the functional relationship between TrkB, cell invasion and plasticity of human NB cells by taking advantage of our validated in vivo chick embryo transplant model. We find that LAN5 (high TrkB) and SHSY5Y (moderate TrkB) human NB cells aggressively invade host embryos and populate typical NC targets, however loss of TrkB function significantly reduces cell invasion. In contrast, NB1643 (low TrkB) cells remain near the transplant site, but over-expression of TrkB leads to significant cell invasion. Invasive NB cells show enhanced expression of genes indicative of the most invasive host NC cells. In contrast, transplanted human NB cells down-regulate known NB tumor initiating and stem cell markers. Human NB cells that remain within the dorsal neural tube transplant also show enhanced expression of cell differentiation genes, resulting in an improved disease outcome as predicted by a computational algorithm. These in vivo data support TrkB as an important biomarker and target to control NB aggressiveness and identify the chick embryonic trunk neural crest microenvironment as a source of signals to drive NB to a less aggressive state, likely acting at the dorsal neural tube.
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Affiliation(s)
| | | | - Connor E Muolo
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | - Jason A Morrison
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | - Thomas E Woolley
- School of Mathematics, Cardiff University, Cathays, Cardiff, CF24, UK
| | - Santiago Schnell
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Paul M Kulesa
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA; Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS, 66160, USA.
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28
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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Barbet V, Broutier L. Future Match Making: When Pediatric Oncology Meets Organoid Technology. Front Cell Dev Biol 2021; 9:674219. [PMID: 34327198 PMCID: PMC8315550 DOI: 10.3389/fcell.2021.674219] [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: 02/28/2021] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
Unlike adult cancers that frequently result from the accumulation in time of mutational “hits” often linked to lifestyle, childhood cancers are emerging as diseases of dysregulated development through massive epigenetic alterations. The ability to reconstruct these differences in cancer models is therefore crucial for better understanding the uniqueness of pediatric cancer biology. Cancer organoids (i.e., tumoroids) represent a promising approach for creating patient-derived in vitro cancer models that closely recapitulate the overall pathophysiological features of natural tumorigenesis, including intra-tumoral heterogeneity and plasticity. Though largely applied to adult cancers, this technology is scarcely used for childhood cancers, with a notable delay in technological transfer. However, tumoroids could provide an unprecedented tool to unravel the biology of pediatric cancers and improve their therapeutic management. We herein present the current state-of-the-art of a long awaited and much needed matchmaking.
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Affiliation(s)
- Virginie Barbet
- Childhood Cancer & Cell Death (C3), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France
| | - Laura Broutier
- Childhood Cancer & Cell Death (C3), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France
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Menard MJ. Loss of Gas7 Is a Key Metastatic Switch in Neuroblastoma. Cancer Res 2021; 81:2815-2816. [PMID: 34087781 DOI: 10.1158/0008-5472.can-21-0783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 11/16/2022]
Abstract
Metastatic spread to distant tissues and organs is responsible for most cancer-related mortalities. Changes in the invasiveness ability of metastatic tumor cells often come with significantly altered gene expression profiles compared with primary tumor cells. Identifying the main actors involved in the metastatic switch of tumor cells is key to proposed new therapeutic approaches. In this issue, the loss of growth-arrest specific 7 is described as one of the main events driving metastatic spread in neuroblastoma.See related article by Dong et al., p. 2995.
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Affiliation(s)
- Marie J Menard
- Department of Neurology, University of California, San Francisco, San Francisco, California.
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31
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Li M, Xu D, Xia X, Ni B, Zhu C, Zhao G, Cao H. Sema3C promotes hepatic metastasis and predicts poor prognosis in gastric adenocarcinoma. J Int Med Res 2021; 49:3000605211009802. [PMID: 33909533 PMCID: PMC8108085 DOI: 10.1177/03000605211009802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Semaphorin 3C (Sema3C) may regulate tumor metastasis and prognosis. We determined the biological roles of Sema3C in the hepatic metastasis of gastric adenocarcinoma and evaluated its clinical significance as a potential biomarker. METHODS Sema3C expression in gastric cancer (GC) cell lines and tissues was measured using RT-qPCR and western blotting. Moreover, Sema3C functions were analyzed using Transwell assays and in vitro metastasis assays in gain- and loss-of-function experiments. Furthermore, the impact of Sema3C on the prognosis of 80 randomly selected patients with GC was investigated by immunohistochemistry. Additionally, the expression of epithelial-mesenchymal transition (EMT) indicators was verified by immunohistochemistry in GC tissues. RESULTS Sema3C expression was significantly upregulated in highly metastatic GC cell lines and tissues. Additionally, Sema3C promoted invasion, migration and hepatic metastasis in GC cells. Moreover, Sema3C expression was positively correlated with clinicopathological features in GC and paired hepatic metastatic tissues, and Sema3C expression was an independent prognostic factor. Finally, Sema3C expression was associated with node metastasis, hepatic metastasis and EMT marker expression. CONCLUSIONS Sema3C may play roles in regulating the EMT and metastasis of gastric adenocarcinoma, highlighting its potential use as a prognostic factor for hepatic metastasis and poor prognosis in gastric adenocarcinoma.
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Affiliation(s)
- Maoran Li
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Danhua Xu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xiang Xia
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Bo Ni
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Hui Cao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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32
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What we can learn from embryos to understand the mesenchymal-to-epithelial transition in tumor progression. Biochem J 2021; 478:1809-1825. [PMID: 33988704 DOI: 10.1042/bcj20210083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/06/2021] [Accepted: 04/23/2021] [Indexed: 12/15/2022]
Abstract
Epithelial plasticity involved the terminal and transitional stages that occur during epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), both are essential at different stages of early embryonic development that have been co-opted by cancer cells to undergo tumor metastasis. These processes are regulated at multiple instances, whereas the post-transcriptional regulation of key genes mediated by microRNAs is gaining major attention as a common and conserved pathway. In this review, we focus on discussing the latest findings of the cellular and molecular basis of the less characterized process of MET during embryonic development, with special attention to the role of microRNAs. Although we take in consideration the necessity of being cautious when extrapolating the obtained evidence, we propose some commonalities between early embryonic development and cancer progression that can shed light into our current understanding of this complex event and might aid in the design of specific therapeutic approaches.
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Lettieri A, Oleari R, Paganoni AJJ, Gervasini C, Massa V, Fantin A, Cariboni A. Semaphorin Regulation by the Chromatin Remodeler CHD7: An Emerging Genetic Interaction Shaping Neural Cells and Neural Crest in Development and Cancer. Front Cell Dev Biol 2021; 9:638674. [PMID: 33869187 PMCID: PMC8047133 DOI: 10.3389/fcell.2021.638674] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
CHD7 is a chromatin remodeler protein that controls gene expression via the formation of multi-protein complexes with specific transcription factors. During development, CHD7 controls several differentiation programs, mainly by acting on neural progenitors and neural crest (NC) cells. Thus, its roles range from the central nervous system to the peripheral nervous system and the organs colonized by NC cells, including the heart. Accordingly, mutated CHD7 is linked to CHARGE syndrome, which is characterized by several neuronal dysfunctions and by malformations of NC-derived/populated organs. Altered CHD7 has also been associated with different neoplastic transformations. Interestingly, recent evidence revealed that semaphorins, a class of molecules involved in developmental and pathological processes similar to those controlled by CHD7, are regulated by CHD7 in a context-specific manner. In this article, we will review the recent insights that support the existence of genetic interactions between these pathways, both during developmental processes and cancer progression.
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Affiliation(s)
- Antonella Lettieri
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Roberto Oleari
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alyssa J J Paganoni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Cristina Gervasini
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Valentina Massa
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alessandro Fantin
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - Anna Cariboni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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Dong Z, Yeo KS, Lopez G, Zhang C, Dankert Eggum EN, Rokita JL, Ung CY, Levee TM, Her ZP, Howe CJ, Hou X, van Ree JH, Li S, He S, Tao T, Fritchie K, Torres-Mora J, Lehman JS, Meves A, Razidlo GL, Rathi KS, Weroha SJ, Look AT, van Deursen JM, Li H, Westendorf JJ, Maris JM, Zhu S. GAS7 Deficiency Promotes Metastasis in MYCN-Driven Neuroblastoma. Cancer Res 2021; 81:2995-3007. [PMID: 33602789 DOI: 10.1158/0008-5472.can-20-1890] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/04/2021] [Accepted: 02/15/2021] [Indexed: 11/16/2022]
Abstract
One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression. SIGNIFICANCE: Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma.See related commentary by Menard, p. 2815.
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Affiliation(s)
- Zhiwei Dong
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Kok Siong Yeo
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Gonzalo Lopez
- Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Cheng Zhang
- Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Erin N Dankert Eggum
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Jo Lynne Rokita
- Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Choong Yong Ung
- Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Taylor M Levee
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Zuag Paj Her
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Cassie J Howe
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Xiaonan Hou
- Departments of Oncology, Radiation Oncology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Janine H van Ree
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Shuai Li
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Shuning He
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Ting Tao
- Children's Hospital, Zhejiang University School of Medicine; National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
| | - Karen Fritchie
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jorge Torres-Mora
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Julia S Lehman
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota
| | - Alexander Meves
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota
| | - Gina L Razidlo
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Komal S Rathi
- Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - S John Weroha
- Departments of Oncology, Radiation Oncology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - A Thomas Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Jan M van Deursen
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Hu Li
- Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Jennifer J Westendorf
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota.,Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | - John M Maris
- Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania
| | - Shizhen Zhu
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota. .,Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
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35
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Kulesa PM, Kasemeier-Kulesa JC, Morrison JA, McLennan R, McKinney MC, Bailey C. Modelling Cell Invasion: A Review of What JD Murray and the Embryo Can Teach Us. Bull Math Biol 2021; 83:26. [PMID: 33594536 DOI: 10.1007/s11538-021-00859-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/08/2021] [Indexed: 12/11/2022]
Abstract
Cell invasion and cell plasticity are critical to human development but are also striking features of cancer metastasis. By distributing a multipotent cell type from a place of birth to distal locations, the vertebrate embryo builds organs. In comparison, metastatic tumor cells often acquire a de-differentiated phenotype and migrate away from a primary site to inhabit new microenvironments, disrupting normal organ function. Countless observations of both embryonic cell migration and tumor metastasis have demonstrated complex cell signaling and interactive behaviors that have long confounded scientist and clinician alike. James D. Murray realized the important role of mathematics in biology and developed a unique strategy to address complex biological questions such as these. His work offers a practical template for constructing clear, logical, direct and verifiable models that help to explain complex cell behaviors and direct new experiments. His pioneering work at the interface of development and cancer made significant contributions to glioblastoma cancer and embryonic pattern formation using often simple models with tremendous predictive potential. Here, we provide a brief overview of advances in cell invasion and cell plasticity using the embryonic neural crest and its ancestral relationship to aggressive cancers that put into current context the timeless aspects of his work.
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Affiliation(s)
- Paul M Kulesa
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA. .,Department of Anatomy and Cell Biology, School of Medicine, University of Kansas, Kansas City, KS, 66160, USA.
| | | | - Jason A Morrison
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | - Rebecca McLennan
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | | | - Caleb Bailey
- Department of Biology, Brigham Young University-Idaho, Rexburg, ID, 83460, USA
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36
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Xu C, Zhang Y, Shen Y, Shi Y, Zhang M, Zhou L. Integrated Analysis Reveals ENDOU as a Biomarker in Head and Neck Squamous Cell Carcinoma Progression. Front Oncol 2021; 10:522332. [PMID: 33614471 PMCID: PMC7894080 DOI: 10.3389/fonc.2020.522332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 12/07/2020] [Indexed: 12/15/2022] Open
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is a leading cancer with high morbidity and mortality worldwide. The aim is to identify genes with clinical significance by integrated bioinformatics analysis and investigate their function in HNSCC. Methods We downloaded and analyzed two gene expression datasets of GSE6631 and GSE107591 to screen differentially expressed genes (DEGs) in HNSCC. Common DEGs were functionally analyzed by Gene ontology and KEGG pathway enrichment analysis. Protein-protein interaction (PPI) network was constructed with STRING database and Cytoscape. ENDOU was overexpressed in FaDu and Cal-27 cell lines, and cell proliferation and migration capability were evaluated with MTT, scratch and transwell assay. The prognostic performance of ENDOU and expression correlation with tumor infiltrates in HNSCC were validated with TCGA HNSCC datasets. Results Ninety-eight genes shared common differential expression in both datasets, with core functions like extracellular matrix organization significantly enriched. 15 genes showed prognostic significance, and COBL and ENDOU serve as independent survival markers in HNSCC. In-vitro ENDOU overexpression inhibited FaDu and Cal-27 cells proliferation and migration, indicating its tumor-suppressing role in HNSCC progression. GSEA analysis indicated ENDOU down-stream pathways like DNA replication, mismatch repair, cell cycle and IL-17 signaling pathway. ENDOU showed relative lower expression in HNSCC, especially HPV-positive HNSCC samples. At last, ENDOU showed negative correlation with tumor purity and tumor infiltrating macrophages, especially M2 macrophages. Conclusion This study identified ENDOU as a biomarker with prognostic significance in HNSCC progression.
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Affiliation(s)
- Chengzhi Xu
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Yunbin Zhang
- Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,Department of Respirology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yupeng Shen
- Department of Otolaryngology-Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, China
| | - Yong Shi
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Ming Zhang
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Liang Zhou
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
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Huang Y, Tejero R, Lee VK, Brusco C, Hannah T, Bertucci TB, Junqueira Alves C, Katsyv I, Kluge M, Foty R, Zhang B, Friedel CC, Dai G, Zou H, Friedel RH. Plexin-B2 facilitates glioblastoma infiltration by modulating cell biomechanics. Commun Biol 2021; 4:145. [PMID: 33514835 PMCID: PMC7846610 DOI: 10.1038/s42003-021-01667-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 01/06/2021] [Indexed: 12/17/2022] Open
Abstract
Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). We show here that GBM cells upregulate guidance receptor Plexin-B2 to gain invasiveness. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes. On a cellular level, Plexin-B2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, thus empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. Correspondingly, gene signatures affected by Plexin-B2 were associated with locomotor regulation, matrix interactions, and cellular biomechanics. On a molecular level, the intracellular Ras-GAP domain contributed to Plexin-B2 function, while the signaling relationship with downstream effectors Rap1/2 appeared variable between GBM stem cell lines, reflecting intertumoral heterogeneity. Our studies establish Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness.
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Affiliation(s)
- Yong Huang
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rut Tejero
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vivian K Lee
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Concetta Brusco
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Theodore Hannah
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Taylor B Bertucci
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Chrystian Junqueira Alves
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Igor Katsyv
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Kluge
- Institut für Informatik, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Ramsey Foty
- Department of Surgery, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Caroline C Friedel
- Institut für Informatik, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Guohao Dai
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Hongyan Zou
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Roland H Friedel
- Friedman Brain Institute, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Xu WL, Shi BJ, Li SL, Yu FX, Guo LN, Li M, Hu ZG, Li GX, Zhou H. Targeted inhibition of myeloid-derived suppressor cells in the tumor microenvironment by low-dose doxorubicin to improve immune efficacy in murine neuroblastoma. Chin Med J (Engl) 2020; 134:334-343. [PMID: 33278092 PMCID: PMC7846436 DOI: 10.1097/cm9.0000000000001234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND High agglomeration of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) impeded therapeutic effects. This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin (DOX) to enhance immune efficacy in NB. METHODS Bagg albino (BALB/c) mice were used as tumor-bearing mouse models by injecting Neuro-2a cells, and MDSCs were eliminated by DOX or dopamine (DA) administration. Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX, 5.0 mg/kg DOX, 50.0 mg/kg DA, and control groups (n = 20). The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition. NB antigen-specific cytotoxic T cells (CTLs) were prepared. Tumor-bearing mice were randomly divided into DOX, CTL, anti-ganglioside (GD2), DOX+CTL, DOX+anti-GD2, and control groups. Following low-dose DOX administration, immunotherapy was applied. The levels of human leukocyte antigen (HLA)-I, CD8, interleukin (IL)-2 and interferon (IFN)-γ in peripheral blood, CTLs, T-helper 1 (Thl)/Th2 cytokines, perforin, granzyme and tumor growth were compared among the groups. The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results. RESULTS The slowest tumor growth (F = 6.095, P = 0.018) and strongest MDSC inhibition (F = 14.632, P = 0.001) were observed in 2.5 mg/kg DOX group. Proliferation of T cells was increased (F = 448.721, P < 0.001) and then decreased (F = 2.047, P = 0.186). After low-dose DOX administration, HLA-I (F = 222.489), CD8 (F = 271.686), Thl/Th2 cytokines, CD4+ and CD8+ lymphocytes, granzyme (F = 2376.475) and perforin (F = 488.531) in tumor, IL-2 (F = 62.951) and IFN-γ (F = 240.709) in peripheral blood of each immunotherapy group were all higher compared with the control group (all of P values < 0.05). The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups. CONCLUSIONS Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering immune efficacy in NB.
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Affiliation(s)
- Wei-Li Xu
- Department of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Bao-Jun Shi
- Department of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Suo-Lin Li
- Department of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Feng-Xue Yu
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Li-Na Guo
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Meng Li
- Department of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Zhi-Gang Hu
- Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Gui-Xin Li
- Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Hui Zhou
- Department of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
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Gonzalez Curto G, Der Vartanian A, Frarma YEM, Manceau L, Baldi L, Prisco S, Elarouci N, Causeret F, Korenkov D, Rigolet M, Aurade F, De Reynies A, Contremoulins V, Relaix F, Faklaris O, Briscoe J, Gilardi-Hebenstreit P, Ribes V. The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition. PLoS Genet 2020; 16:e1009164. [PMID: 33175861 PMCID: PMC7682867 DOI: 10.1371/journal.pgen.1009164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 11/23/2020] [Accepted: 10/02/2020] [Indexed: 12/18/2022] Open
Abstract
The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAX-FOXO1s. Our data demonstrate that PAX-FOXO1s, but not wild-type PAX3 or PAX7, trigger the trans-differentiation of neural cells into FP-RMS-like cells with myogenic characteristics. In parallel, PAX-FOXO1s remodel the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, expression of PAX-FOXO1s, similar to wild-type PAX3/7, reduce the levels of CDK-CYCLIN activity and increase the fraction of cells in G1. Introduction of CYCLIN D1 or MYCN overcomes this PAX-FOXO1-mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism that can explain the apparent limited oncogenicity of PAX-FOXO1 fusion transcription factors. They are also consistent with certain clinical reports indicative of a neural origin of FP-RMS.
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Affiliation(s)
| | | | | | - Line Manceau
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Lorenzo Baldi
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Selene Prisco
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Nabila Elarouci
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Frédéric Causeret
- Université de Paris, Imagine Institute, Team Genetics and Development of the Cerebral Cortex, Paris, France
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Paris, France
| | - Daniil Korenkov
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Muriel Rigolet
- Univ Paris Est Créteil, INSERM, EnVA, EFS, IMRB, Créteil, France
| | - Frédéric Aurade
- Univ Paris Est Créteil, INSERM, EnVA, EFS, IMRB, Créteil, France
- Sorbonne Université, INSERM, UMRS974, Center for Research in Myology, Paris, France
| | - Aurélien De Reynies
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Vincent Contremoulins
- ImagoSeine core facility of Institut Jacques Monod and member of France-BioImaging, France
| | - Frédéric Relaix
- Univ Paris Est Créteil, INSERM, EnVA, EFS, IMRB, Créteil, France
| | - Orestis Faklaris
- ImagoSeine core facility of Institut Jacques Monod and member of France-BioImaging, France
| | - James Briscoe
- The Francis Crick Institute, 1 Midland Road, London, United Kingdom
| | | | - Vanessa Ribes
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
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Gross-Amat O, Guillen M, Gimeno JP, Salzet M, Lebonvallet N, Misery L, Auxenfans C, Nataf S. Molecular Mapping of Hydrogen Sulfide Targets in Normal Human Keratinocytes. Int J Mol Sci 2020; 21:E4648. [PMID: 32629886 PMCID: PMC7369889 DOI: 10.3390/ijms21134648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/17/2020] [Accepted: 06/26/2020] [Indexed: 12/11/2022] Open
Abstract
Although sulfur-rich thermal waters have ancestrally been used in the context of dermatological conditions, a global mapping of the molecular effects exerted by H2S on human keratinocytes is still lacking. To fill this knowledge gap, we subjected cultured human keratinocytes to distinct amounts of the non-gaseous hydrogen sulfur donor NaHS. We first checked that H2S accumulated in the cytoplasm of keratinocytes under our experimental conditions andused a combination of proteomics, genomics and biochemical approaches to unravel functionally relevant H2S targets in human keratinocytes. We found that the identified targets fall into two main categories: (i) the oxidative stress response molecules superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1) and culin 3 (CUL3) and (ii) the chemokines interleukin-8 (IL-8) and CXCL2. Interestingly, NaHS also stimulated the caspase-1 inflammasome pathway, leading to increased secretion of the pro-inflammatory molecule interleukin-18 (IL-18). Interestingly, the secretion of interleukin-1 beta (IL-1β) was only modestly impacted by NaHS exposure despite a significant accumulation of IL-1β pro-form. Finally, we observed that NaHS significantly hampered the growth of human keratinocyte progenitors and stem cells cultured under clonogenic conditions or as epidermal cell sheets. We conclude that H2S exerts specific molecular effects on normal human keratinocytes.
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Affiliation(s)
- Olivia Gross-Amat
- Lyon-Est School of Medicine, University Claude Bernard Lyon-1, 69100 Villeurbanne, France; (M.G.); (S.N.)
- Bank of Tissues and Cells, Lyon University Hospital (Hospices Civils de Lyon), 69003 Lyon, France;
- CarMeN Laboratory, INSERM U1060, INRA U1397, INSA de Lyon, 69600 Oullins, France
| | - Marine Guillen
- Lyon-Est School of Medicine, University Claude Bernard Lyon-1, 69100 Villeurbanne, France; (M.G.); (S.N.)
| | - Jean-Pascal Gimeno
- Inserm, CHRU Lille, U-1192-Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, University of Lille, F-59000 Lille, France; (J.-P.G.); (M.S.)
| | - Michel Salzet
- Inserm, CHRU Lille, U-1192-Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, University of Lille, F-59000 Lille, France; (J.-P.G.); (M.S.)
| | - Nicolas Lebonvallet
- Laboratory of Epithelial-Neural Interactions, University of Brest, LIEN, 29200 Brest, France; (N.L.); (L.M.)
| | - Laurent Misery
- Laboratory of Epithelial-Neural Interactions, University of Brest, LIEN, 29200 Brest, France; (N.L.); (L.M.)
- Department of dermatology, Brest University Hospital (CHU de Brest), 29200 Brest, France
| | - Céline Auxenfans
- Bank of Tissues and Cells, Lyon University Hospital (Hospices Civils de Lyon), 69003 Lyon, France;
- Tissue Biology and Therapeutic Engineering Laboratory, UMR 5305, 69007 Lyon, France
| | - Serge Nataf
- Lyon-Est School of Medicine, University Claude Bernard Lyon-1, 69100 Villeurbanne, France; (M.G.); (S.N.)
- Bank of Tissues and Cells, Lyon University Hospital (Hospices Civils de Lyon), 69003 Lyon, France;
- CarMeN Laboratory, INSERM U1060, INRA U1397, INSA de Lyon, 69600 Oullins, France
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41
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Olivera GG, Yáñez Y, Gargallo P, Sendra L, Aliño SF, Segura V, Sanz MÁ, Cañete A, Castel V, Font De Mora J, Hervás D, Berlanga P, Herrero MJ. MTHFR and VDR Polymorphisms Improve the Prognostic Value of MYCN Status on Overall Survival in Neuroblastoma Patients. Int J Mol Sci 2020; 21:E2714. [PMID: 32295184 PMCID: PMC7215604 DOI: 10.3390/ijms21082714] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/27/2020] [Accepted: 04/10/2020] [Indexed: 12/26/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in Pharmacogenetics can play an important role in the outcomes of the chemotherapy treatment in Neuroblastoma, helping doctors maximize efficacy and minimize toxicity. Employing AgenaBioscience MassArray, 96 SNPs were genotyped in 95 patients looking for associations of SNP with response to induction therapy (RIT) and grade 3-4 toxicities, in High Risk patients. Associations of SNPs with overall (OS) and event-free (EFS) survival in the whole cohort were also explored. Cox and logistic regression models with Elastic net penalty were employed. Association with grade 3-4 gastrointestinal and infectious toxicities was found for 8 different SNPs. Better RIT was correlated with rs726501 AG, rs3740066 GG, rs2010963 GG and rs1143684 TT (OR = 2.87, 1.79, 1.23, 1.14, respectively). EFS was affected by rs2032582, rs4880, rs3814058, rs45511401, rs1544410 and rs6539870. OS was influenced by rs 1801133, rs7186128 and rs1544410. Remarkably, rs1801133 in MTHFR (p = 0.02) and rs1544410 in VDR (p = 0.006) also added an important predictive value for OS to the MYCN status, with a more accurate substratification of the patients. Although validation studies in independent cohorts will be required, the data obtained supports the utility of Pharmacogenetics for predicting Neuroblastoma treatment outcomes.
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Affiliation(s)
- Gladys G. Olivera
- Pharmacogenetics Platform, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (G.G.O.); (M.J.H.)
- Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
| | - Yania Yáñez
- Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (Y.Y.)
| | - Pablo Gargallo
- Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain (A.C.)
| | - Luis Sendra
- Pharmacogenetics Platform, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (G.G.O.); (M.J.H.)
- Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
| | - Salvador F. Aliño
- Pharmacogenetics Platform, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (G.G.O.); (M.J.H.)
- Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
- Clinical Pharmacology Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain
| | - Vanessa Segura
- Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain (A.C.)
| | - Miguel Ángel Sanz
- Hematology and Hemotherapy Service, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain
| | - Adela Cañete
- Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain (A.C.)
| | - Victoria Castel
- Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain (A.C.)
| | - Jaime Font De Mora
- Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (Y.Y.)
| | - David Hervás
- Data Science, Biostatistics and Bioinformatics Platform, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Pablo Berlanga
- Department of Pediatric and Adolescent Oncology, Institute Gustave Roussy Center, 94800 Villejuif, France;
| | - María José Herrero
- Pharmacogenetics Platform, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (G.G.O.); (M.J.H.)
- Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
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Darrigrand JF, Valente M, Comai G, Martinez P, Petit M, Nishinakamura R, Osorio DS, Renault G, Marchiol C, Ribes V, Cadot B. Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation. eLife 2020; 9:e50325. [PMID: 32105214 PMCID: PMC7069721 DOI: 10.7554/elife.50325] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 02/26/2020] [Indexed: 02/07/2023] Open
Abstract
The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac outflow tract (OFT) septation, is a sensitive developmental process accounting for 10% of all congenital anomalies. Neural Crest Cells (NCC) colonising the heart condensate along the primitive endocardial tube and force its scission into two tubes. Here, we show that NCC aggregation progressively decreases along the OFT distal-proximal axis following a BMP signalling gradient. Dullard, a nuclear phosphatase, tunes the BMP gradient amplitude and prevents NCC premature condensation. Dullard maintains transcriptional programs providing NCC with mesenchymal traits. It attenuates the expression of the aggregation factor Sema3c and conversely promotes that of the epithelial-mesenchymal transition driver Twist1. Altogether, Dullard-mediated fine-tuning of BMP signalling ensures the timed and progressive zipper-like closure of the OFT by the NCC and prevents the formation of a heart carrying the congenital abnormalities defining the tetralogy of Fallot.
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Affiliation(s)
| | - Mariana Valente
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure team, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737ParisFrance
| | - Glenda Comai
- Stem Cells and Development, Department of Developmental & Stem Cell Biology, CNRS UMR 3738, Institut PasteurParisFrance
| | - Pauline Martinez
- INSERM - Sorbonne Université UMR974 - Center for Research in MyologyParisFrance
| | - Maxime Petit
- Unité Lymphopoïèse – INSERM U1223, Institut PasteurParisFrance
| | | | - Daniel S Osorio
- Cytoskeletal Dynamics Lab, Institute for Molecular and Cellular Biology, Instituto de Investigação e Inovação em Saúde, Universidade do PortoPortoPortugal
| | - Gilles Renault
- Université de Paris, Institut Cochin, INSERM, CNRSParisFrance
| | - Carmen Marchiol
- Université de Paris, Institut Cochin, INSERM, CNRSParisFrance
| | - Vanessa Ribes
- Universite de Paris, Institut Jacques MonodCNRSParisFrance
| | - Bruno Cadot
- INSERM - Sorbonne Université UMR974 - Center for Research in MyologyParisFrance
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Wang Y, Liu Y, Du X, Ma H, Yao J. The Anti-Cancer Mechanisms of Berberine: A Review. Cancer Manag Res 2020; 12:695-702. [PMID: 32099466 PMCID: PMC6996556 DOI: 10.2147/cmar.s242329] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 01/22/2020] [Indexed: 12/12/2022] Open
Abstract
Berberine (BBR) has been extensively studied in vivo and vitro experiments. BBR inhibits cell proliferation by regulating cell cycle and cell autophagy, and promoting cell apoptosis. BBR also inhibits cell invasion and metastasis by suppressing EMT and down-regulating the expression of metastasis-related proteins and signaling pathways. In addition, BBR inhibits cell proliferation by interacting with microRNAs and suppressing telomerase activity. BBR exerts its anti-inflammation and antioxidant properties, and also regulates tumor microenvironment. This review emphasized that BBR as a potential anti-inflammation and antioxidant agent, also as an effective immunomodulator, is expected to be widely used in clinic for cancer therapy.
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Affiliation(s)
- Ye Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Yanfang Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Xinyang Du
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Hong Ma
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Jing Yao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
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Vega FM, Colmenero-Repiso A, Gómez-Muñoz MA, Rodríguez-Prieto I, Aguilar-Morante D, Ramírez G, Márquez C, Cabello R, Pardal R. CD44-high neural crest stem-like cells are associated with tumour aggressiveness and poor survival in neuroblastoma tumours. EBioMedicine 2019; 49:82-95. [PMID: 31685444 PMCID: PMC6945283 DOI: 10.1016/j.ebiom.2019.10.041] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
Background Neuroblastoma is a paediatric tumour originated from sympathoadrenal precursors and characterized by its heterogeneity and poor outcome in advanced stages. Intra-tumoral cellular heterogeneity has emerged as an important feature in neuroblastoma, with a potential major impact on tumour aggressiveness and response to therapy. CD44 is an adhesion protein involved in tumour progression, metastasis and stemness in different cancers; however, there has been controversies about the significance of CD44 expression in neuroblastoma and its relationship with tumour progression. Methods We have performed transcriptomic analysis on patient tumour samples studying the outcome of patients with high CD44 expression. Adhesion, invasion and proliferation assays were performed in sorted CD44high neuroblastoma cells. Tumoursphere cultures have been used to enrich in undifferentiated stem-like cells and to asses self-renewal and differentiation potential. We have finally performed in vivo tumorigenic assays on cell line-derived or Patient-derived xenografts. Findings We show that high CD44 expression is associated with low survival in high-grade human neuroblastoma, independently of MYCN amplification. CD44 is expressed in a cell population with neural crest stem-like features, and with the capacity to generate multipotent, undifferentiated tumourspheres in culture. These cells are more invasive and proliferative in vitro. CD44 positive cells obtained from tumours are more tumorigenic and metastatic, giving rise to aggressive neuroblastic tumours at high frequency upon transplantation. Interpretation We describe an unexpected intra-tumoural heterogeneity within cellular entities expressing CD44 in neuroblastoma, and propose that CD44 has a role in neural crest stem-like undifferentiated cells, which can contribute to tumorigenesis and malignancy in this type of cancer. Funding Research supported by grants from the “Asociación Española contra el Cáncer” (AECC), the Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P), and the European Research Council (ERC Starting Grant to RP).
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Affiliation(s)
- Francisco M Vega
- Dpto. de Biología Celular, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41012 Seville, Spain.
| | - Ana Colmenero-Repiso
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla 41013 Seville, Spain
| | - María A Gómez-Muñoz
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla 41013 Seville, Spain
| | - Ismael Rodríguez-Prieto
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla 41013 Seville, Spain
| | - Diana Aguilar-Morante
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla 41013 Seville, Spain
| | - Gema Ramírez
- Unidad de Oncología Pediátrica, Hospital Universitario Virgen del Rocío, Spain
| | - Catalina Márquez
- Unidad de Oncología Pediátrica, Hospital Universitario Virgen del Rocío, Spain
| | - Rosa Cabello
- Unidad de Cirugía Pediátrica, Hospital Universitario Virgen del Rocío, Spain
| | - Ricardo Pardal
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla 41013 Seville, Spain.
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Liu R, Shuai Y, Luo J, Zhang Z. SEMA3C Promotes Cervical Cancer Growth and Is Associated With Poor Prognosis. Front Oncol 2019; 9:1035. [PMID: 31649890 PMCID: PMC6794562 DOI: 10.3389/fonc.2019.01035] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 09/24/2019] [Indexed: 12/24/2022] Open
Abstract
Introduction: Aberrant activation of Semaphorin3C(SEMA3C) is widespread in human cancers. We aimed to analyze SEMA3C expression in cervical cancer and investigate the role of SEMA3C in cervical cancer and its underlying mechanism, which is important for exploring new therapeutic targets and prognostic factors. Materials and Methods: The expression of SEMA3C was examined in paraffin-embedded cervical cancer specimens. In vivo and in vitro assays were performed to validate the effect of SEMA3C on cervical cancer cell proliferation and p-ERK pathway activation. Gene Set Enrichment Analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data set. Results: SEMA3C expression was associated with poor survival in both the TCGA cohort and our cohort. Silencing of SEMA3C suppressed cervical cancer cell proliferation, colony formation ability, and the activation of the p-ERK signaling pathway in vitro. SEMA3C depletion inhibited tumor growth in vitro. GSEA also showed that the epithelial mesenchymal transition (EMT), TGFβ signaling pathway, angiogenesis, and extracellular matrix (ECM) receptor interactions are associated with a high SEMA3C expression phenotype. Conclusion: SEMA3C is correlated with poor prognosis of cervical cancer patients and promotes tumor growth via the activation of the p-ERK pathway.
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Affiliation(s)
- Ruoyan Liu
- Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanjie Shuai
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Maxillofacial and Otorhinolaryngology Oncology and Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Jingtao Luo
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Maxillofacial and Otorhinolaryngology Oncology and Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Ze Zhang
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Maxillofacial and Otorhinolaryngology Oncology and Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
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46
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Live Cell Imaging Supports a Key Role for Histone Deacetylase as a Molecular Target during Glioblastoma Malignancy Downgrade through Tumor Competence Modulation. JOURNAL OF ONCOLOGY 2019; 2019:9043675. [PMID: 31531023 PMCID: PMC6720048 DOI: 10.1155/2019/9043675] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 07/03/2019] [Indexed: 11/21/2022]
Abstract
Glioblastoma (GBM) is the most aggressive tumor of the central nervous system, and the identification of the mechanisms underlying the biological basis of GBM aggressiveness is essential to develop new therapies. Due to the low prognosis of GBM treatment, different clinical studies are in course to test the use of histone deacetylase inhibitors (iHDACs) in anticancer cocktails. Here, we seek to investigate the impact of HDAC activity on GBM cell behavior and plasticity by live cell imaging. We pharmacologically knock down HDAC activity using two different inhibitors (TSA and SAHA) in two different tumor cell types: a commercial GBM cell line (U87-MG) and primary tumor (GBM011). Upon 72 hours of in vitro iHDAC treatment, GBM cells presented a very unusual elongated cell shape due to tunneling tube formation and independent on TGF-β signaling epithelial to mesenchymal transition. Live cell imaging revealed that voltage-sensitive Ca++ signaling was disrupted upon HDAC activity blockade. This behavior was coupled to vimentin and connexin 43 gene expression downregulation, suggesting that HDAC activity blockade downgrades GBM aggressiveness mostly due to tumor cell competence and plasticity modulation in vitro. To test this hypothesis and access whether iHDACs would modulate tumor cell behavior and plasticity to properly respond to environmental cues in vivo, we xenografted GBM oncospheres in the chick developing the neural tube. Remarkably, upon 5 days in the developing neural tube, iHDAC-treated GBM cells ectopically expressed HNK-1, a tumor-suppressor marker tightly correlated to increased survivor of patients. These results describe, for the first time in the literature, the relevance of iHDACs for in vivo tumor cell morphology and competence to properly respond to environmental cues. Ultimately, our results highlight the relevance of chromatin remodeling for tumor cell plasticity and shed light on clinical perspectives aiming the epigenome as a relevant therapeutic target for GBM therapy.
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47
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Delloye-Bourgeois C, Castellani V. Hijacking of Embryonic Programs by Neural Crest-Derived Neuroblastoma: From Physiological Migration to Metastatic Dissemination. Front Mol Neurosci 2019; 12:52. [PMID: 30881286 PMCID: PMC6405627 DOI: 10.3389/fnmol.2019.00052] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/12/2019] [Indexed: 12/12/2022] Open
Abstract
In the developing organism, complex molecular programs orchestrate the generation of cells in adequate numbers, drive them to migrate along the correct pathways towards appropriate territories, eliminate superfluous cells, and induce terminal differentiation of survivors into the appropriate cell-types. Despite strict controls constraining developmental processes, malignancies can emerge in still immature organisms. This is the case of neuroblastoma (NB), a highly heterogeneous disease, predominantly affecting children before the age of 5 years. Highly metastatic forms represent half of the cases and are diagnosed when disseminated foci are detectable. NB arise from a transient population of embryonic cells, the neural crest (NC), and especially NC committed to the establishment of the sympatho-adrenal tissues. The NC is generated at the dorsal edge of the neural tube (NT) of the vertebrate embryo, under the action of NC specifier gene programs. NC cells (NCCs) undergo an epithelial to mesenchymal transition, and engage on a remarkable journey in the developing embryo, contributing to a plethora of cell-types and tissues. Various NCC sub-populations and derived lineages adopt specific migratory behaviors, moving individually as well as collectively, exploiting the different embryonic substrates they encounter along their path. Here we discuss how the specific features of NCC in development are re-iterated during NB metastatic behaviors.
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Affiliation(s)
- Céline Delloye-Bourgeois
- University of Lyon, University of Lyon 1 Claude Bernard Lyon 1, NeuroMyoGene Institute, CNRS UMR5310, INSERM U1217, Lyon, France
| | - Valérie Castellani
- University of Lyon, University of Lyon 1 Claude Bernard Lyon 1, NeuroMyoGene Institute, CNRS UMR5310, INSERM U1217, Lyon, France
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48
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Hui DHF, Tam KJ, Jiao IZF, Ong CJ. Semaphorin 3C as a Therapeutic Target in Prostate and Other Cancers. Int J Mol Sci 2019; 20:E774. [PMID: 30759745 PMCID: PMC6386986 DOI: 10.3390/ijms20030774] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 02/05/2019] [Accepted: 02/08/2019] [Indexed: 12/21/2022] Open
Abstract
The semaphorins represent a large family of signaling molecules with crucial roles in neuronal and cardiac development. While normal semaphorin function pertains largely to development, their involvement in malignancy is becoming increasingly evident. One member, Semaphorin 3C (SEMA3C), has been shown to drive a number of oncogenic programs, correlate inversely with cancer prognosis, and promote the progression of multiple different cancer types. This report surveys the body of knowledge surrounding SEMA3C as a therapeutic target in cancer. In particular, we summarize SEMA3C's role as an autocrine andromedin in prostate cancer growth and survival and provide an overview of other cancer types that SEMA3C has been implicated in including pancreas, brain, breast, and stomach. We also propose molecular strategies that could potentially be deployed against SEMA3C as anticancer agents such as biologics, small molecules, monoclonal antibodies and antisense oligonucleotides. Finally, we discuss important considerations for the inhibition of SEMA3C as a cancer therapeutic agent.
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Affiliation(s)
- Daniel H F Hui
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
| | - Kevin J Tam
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
| | - Ivy Z F Jiao
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
| | - Christopher J Ong
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
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Celià-Terrassa T, Kang Y. Metastatic niche functions and therapeutic opportunities. Nat Cell Biol 2018; 20:868-877. [PMID: 30050120 DOI: 10.1038/s41556-018-0145-9] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/13/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022]
Abstract
Metastasis is an inefficient process, especially during colonization at a distant organ. This bottleneck underlies the importance of the metastatic niche for seeding and outgrowth of metastases. Here, we classify the common functions of different metastatic niches: anchorage, survival support, protection from external insults, licensing proliferation and outgrowth. We highlight the emerging role of the metastatic niche in maintaining cancer stemness and promoting immune evasion, and discuss therapeutic opportunities against the metastatic niche.
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Affiliation(s)
- Toni Celià-Terrassa
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.,Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
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Semaphorin 3C and Its Receptors in Cancer and Cancer Stem-Like Cells. Biomedicines 2018; 6:biomedicines6020042. [PMID: 29642487 PMCID: PMC6027460 DOI: 10.3390/biomedicines6020042] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 03/27/2018] [Accepted: 04/03/2018] [Indexed: 01/13/2023] Open
Abstract
Neurodevelopmental programs are frequently dysregulated in cancer. Semaphorins are a large family of guidance cues that direct neuronal network formation and are also implicated in cancer. Semaphorins have two kinds of receptors, neuropilins and plexins. Besides their role in development, semaphorin signaling may promote or suppress tumors depending on their context. Sema3C is a secreted semaphorin that plays an important role in the maintenance of cancer stem-like cells, promotes migration and invasion, and may facilitate angiogenesis. Therapeutic strategies that inhibit Sema3C signaling may improve cancer control. This review will summarize the current research on the Sema3C pathway and its potential as a therapeutic target.
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