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A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medulloblastoma metastasis.
Zou, Han; 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, Olivier; Ly, Michelle; Fellows-Mayle, Wendy; Xi, Guifa; Tomita, Tadanori; Resnick, Adam C; Mack, Stephen C; Raabe, Eric H; Eberhart, Charles G; Sun, Dandan; Stronach, Beth E; 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; Hainer, Sarah J; Taylor, Michael D; Hu, Baoli.
Affiliation
  • Zou H; Xiangya School of Medicine, Central South University, Changsha, China.
  • Poore B; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
  • Brown EE; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Changsha, China.
  • Qian J; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Xie B; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Asimakidou E; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Razskazovskiy V; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Ayrapetian D; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
  • Sharma V; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Xia S; Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
  • Liu F; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Chen A; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Guan Y; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Li Z; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Wanggou S; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Saulnier O; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Ly M; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Fellows-Mayle W; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Xi G; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
  • Tomita T; Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • Resnick AC; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Mack SC; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Raabe EH; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Eberhart CG; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Sun D; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Stronach BE; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Agnihotri S; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
  • Kohanbash G; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Lu S; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • Herrup K; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Rich JN; Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Gittes GK; Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Broniscer A; Center for Data-Driven Discovery in Biomedicine, Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Hu Z; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Li X; Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Pollack IF; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Friedlander RM; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Hainer SJ; Office of Research, University of Pittsburgh Health Sciences, Pittsburgh, PA, USA.
  • Taylor MD; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
  • Hu B; John G. Rangos Sr Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Nat Cell Biol ; 25(3): 493-507, 2023 03.
Article in En | MEDLINE | ID: mdl-36849558
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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Full text: 1 Database: MEDLINE Main subject: Cerebellar Neoplasms / Medulloblastoma Type of study: Prognostic_studies Limits: Humans Language: En Year: 2023 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Cerebellar Neoplasms / Medulloblastoma Type of study: Prognostic_studies Limits: Humans Language: En Year: 2023 Type: Article