A neurodevelopmental epigenetic programme mediated by SMARCD3–DAB1–Reelin signalling is hijacked to promote medulloblastoma metastasis
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Published:2023-02-27
Issue:3
Volume:25
Page:493-507
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ISSN:1465-7392
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Container-title:Nature Cell Biology
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language:en
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Short-container-title:Nat Cell Biol
Author:
Zou HanORCID, Poore Bradley, Brown Emily E., Qian Jieqi, Xie Bin, Asimakidou Evridiki, Razskazovskiy Vladislav, Ayrapetian Deanna, Sharma Vaibhav, Xia Shunjin, Liu Fei, Chen Apeng, Guan Yongchang, Li Zhengwei, Wanggou Siyi, Saulnier OlivierORCID, Ly Michelle, Fellows-Mayle Wendy, Xi GuifaORCID, Tomita Tadanori, Resnick Adam C., Mack Stephen C.ORCID, Raabe Eric H., Eberhart Charles G., Sun Dandan, Stronach Beth E.ORCID, Agnihotri Sameer, Kohanbash Gary, Lu Songjian, Herrup Karl, Rich Jeremy N., Gittes George K., Broniscer Alberto, Hu Zhongliang, Li Xuejun, Pollack Ian F., Friedlander Robert M.ORCID, Hainer Sarah J.ORCID, Taylor Michael D.ORCID, Hu BaoliORCID
Abstract
AbstractHow abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin–DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke Matthew Larson Foundation for Pediatric Brain Tumors V Foundation for Cancer Research
Publisher
Springer Science and Business Media LLC
Reference69 articles.
1. Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016). 2. Zou, H., Poore, B., Broniscer, A., Pollack, I. F. & Hu, B. Molecular heterogeneity and cellular diversity: implications for precision treatment in medulloblastoma. Cancers https://doi.org/10.3390/cancers12030643 (2020). 3. Taylor, M. D. et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123, 465–472 (2012). 4. Cavalli, F. M. G. et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 31, 737–754.e6 (2017). 5. Northcott, P. A. et al. Medulloblastomics: the end of the beginning. Nat. Rev. Cancer 12, 818–834 (2012).
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