2. Academic Validation
  3. A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medulloblastoma metastasis

A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medulloblastoma metastasis

  • Nat Cell Biol. 2023 Feb 27. doi: 10.1038/s41556-023-01093-0.
Han Zou 1 2 3 4 5,  Bradley Poore 4 5,  Emily E Brown 6,  Jieqi Qian 5,  Bin Xie 7,  Evridiki Asimakidou 4 5,  Vladislav Razskazovskiy 4 5,  Deanna Ayrapetian 4 5,  Vaibhav Sharma 4 5,  Shunjin Xia 2,  Fei Liu 8,  Apeng Chen 4 5,  Yongchang Guan 4 5,  Zhengwei Li 4 5,  Siyi Wanggou 2,  Olivier Saulnier 9,  Michelle Ly 9,  Wendy Fellows-Mayle 4,  Guifa Xi 10,  Tadanori Tomita 10,  Adam C Resnick 11,  Stephen C Mack 12,  Eric H Raabe 13,  Charles G Eberhart 14,  Dandan Sun 15,  Beth E Stronach 16,  Sameer Agnihotri 4 5 17,  Gary Kohanbash 4 5 17,  Songjian Lu 18,  Karl Herrup 19,  Jeremy N Rich 15 17,  George K Gittes 5 20 21,  Alberto Broniscer 5 17 21,  Zhongliang Hu 7,  Xuejun Li 2 3,  Ian F Pollack 4 5 17,  Robert M Friedlander 4,  Sarah J Hainer 22 23,  Michael D Taylor 24,  Baoli Hu 25 26 27 28
Affiliations

Affiliations

  • 1 Xiangya School of Medicine, Central South University, Changsha, China.
  • 2 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
  • 3 Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Changsha, China.
  • 4 Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 6 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
  • 8 Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • 9 Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 10 Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 11 Center for Data-Driven Discovery in Biomedicine, Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 12 Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 13 Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 14 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 15 Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 16 Office of Research, University of Pittsburgh Health Sciences, Pittsburgh, PA, USA.
  • 17 UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 18 Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA.
  • 19 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 20 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 21 Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 22 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 23 UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
  • 24 Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. [email protected].
  • 25 Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 26 John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 27 UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
  • 28 Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
PMID: 36849558 DOI: 10.1038/s41556-023-01093-0
Abstract

How 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.

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