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<p>Medulloblastoma constitutes a molecularly diverse group of malignant embryonal brain tumors. Sonic hedgehog molecular group of medulloblastoma (SHH-MB) is a highly heterogeneous tumor entity, characterized by constitutive activation of the SHH signaling pathway. Due to lack of suitable cell line models, little is known about genetic dependencies in SHH-MB outside of the SHH pathway. By performing a CRISPR-Cas9 dropout screen in SMB21 cells derived from SHH-MB in <i>Ptch</i><sup><i>+/−</i></sup> mice, we aimed to identify genetic vulnerabilities in SHH-MB. Among the top scored gene hits, members of the SNF2-family of ATP-dependent chromatin remodelers including <i>Smarca5</i> emerged as genetic dependencies in SHH-MB, and we validate that <i>Smarca5</i> knockout inhibits SHH pathway activation and SHH-MB cell proliferation. Additional genetic ablation experiments <i>in vivo</i> revealed that conditional deletion of <i>Smarca5</i> in cerebellar granule cell neuron precursors (GCNPs), the cell origin of SHH-MB, significantly reduces the proliferative capacity of GCNPs and leads to cerebellar hypoplasia in mice. Furthermore, loss of <i>Smarca5</i> in GCNPs in an established mouse model of SHH-MB results in prolonged survival of tumor bearing mice. Our data underline the critical role of SMARCA5 during the development of the cerebellum and the pathogenesis of SHH-MB.</p>

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SMARCA5 is required for the development of granule cell neuron precursors and Sonic Hedgehog Medulloblastoma growth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月18日

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  • Foteini Tsiami,
  • Layla Drwesh,
  • Surender Surender,
  • Julia Fitzgerald,
  • Jens Schittenhelm,
  • David J. Picketts,
  • Rosalind A. Segal,
  • Ghazaleh Tabatabai,
  • Daniel J. Merk

摘要

Medulloblastoma constitutes a molecularly diverse group of malignant embryonal brain tumors. Sonic hedgehog molecular group of medulloblastoma (SHH-MB) is a highly heterogeneous tumor entity, characterized by constitutive activation of the SHH signaling pathway. Due to lack of suitable cell line models, little is known about genetic dependencies in SHH-MB outside of the SHH pathway. By performing a CRISPR-Cas9 dropout screen in SMB21 cells derived from SHH-MB in Ptch+/− mice, we aimed to identify genetic vulnerabilities in SHH-MB. Among the top scored gene hits, members of the SNF2-family of ATP-dependent chromatin remodelers including Smarca5 emerged as genetic dependencies in SHH-MB, and we validate that Smarca5 knockout inhibits SHH pathway activation and SHH-MB cell proliferation. Additional genetic ablation experiments in vivo revealed that conditional deletion of Smarca5 in cerebellar granule cell neuron precursors (GCNPs), the cell origin of SHH-MB, significantly reduces the proliferative capacity of GCNPs and leads to cerebellar hypoplasia in mice. Furthermore, loss of Smarca5 in GCNPs in an established mouse model of SHH-MB results in prolonged survival of tumor bearing mice. Our data underline the critical role of SMARCA5 during the development of the cerebellum and the pathogenesis of SHH-MB.