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.

神经发育异常与髓母细胞瘤 (MB)（最常见的胚胎肿瘤类型）的肿瘤侵袭性之间的关系仍然难以捉摸。在这里，我们发现了一个神经发育表观基因组程序，该程序被劫持以诱导 MB 转移传播。使用我们新生成的数据对集成的公开可用数据集进行无监督分析表明，SMARCD3（也称为 BAF60C）通过在DAB1位点协调顺式调控元件来调节浦肯野细胞迁移和 MB 转移中的 Disabled 1 (DAB1) 介导的 Reelin 信号。我们进一步确定了一组核心转录因子，zeste 同系物 2 (EZH2) 的增强子和核因子 I X (NFIX)，与SMARCD3的顺式调控元件协调形成染色质中枢的基因座，以控制发育中的小脑和转移性 MB 中的 SMARCD3 表达。增加的 SMARCD3 表达激活 Reelin–DAB1 介导的 Src 激酶信号，导致 MB 对 Src 抑制反应。这些数据加深了我们对神经发育编程如何影响疾病进展的理解，并为 MB 患者提供了一种潜在的治疗选择。