SMARCD3's Role in Purkinje Cell Migration and Medulloblastoma Metastasis

Medulloblastoma (MB) is a heterogeneous brain tumor arising in the cerebellum and is the most common malignant pediatric brain tumor. Group 3, one of four molecular MB subgroups (WNT, SHH, Group 3, and Group 4), is the most aggressive and malignant type in children, usually characterized by metastasis at diagnosis. In this study, we identify that SMARCD3/BAF60c (SMARCD3 hereafter), a core component of the SWI/SNF chromatin-remodeling complexes, is highly expressed in Group 3 MB and Purkinje cells (PCs) of the developing cerebellum. Elevated SMARCD3 expression is associated with poorer patient outcomes, MB metastasis, and activation of the Disabled1 (DAB1)-Reelin signaling pathway that is required for PC migration and positioning during cerebellar development. Conditional SMARCD3 deletion in early PCs results in embryonic and early postnatal lethality in mice, and the surviving animals exhibit significant deficits in motor coordination and balance. Immunostaining of SMARCD3 deleted murine cerebellar tissue shows disorganized PC alignment and reduced dendritic branching, confirming the critical role of the SMARCD3-Reelin pathway function in PC migration, positioning, and maturation. These data demonstrate that the SMARCD3-associated SWI/SNF chromatin-remodeling complex regulates Reelin signaling pathway in PC migration and positioning during cerebellar development; however, this neurodevelopmental program is hijacked to promote MB metastatic dissemination. To further understand this mechanism, we analyzed spatiotemporal gene expression and chromatin accessibility data of the human and mouse cerebellum, noting the SMARCD3/Reelin signaling decreased in the mature cerebellum, but is highly upregulated in metastatic medulloblastoma. The study provides compelling functional evidence of SMARCD3 and the associated SWI/SNF complexes’ involvement in cerebellar development, tumor metastasis, and the molecular connections between early brain development and tumorigenesis, offering new rationales for the development of innovative therapies for patients with MB. Citation Format: Yash Patel, Han Zou, Allen Zheng, Anjali Talluru, Nirja Divekar, Chaim Sneiderman, Meghana Dodda, Katie Dietrich, Siheng Chao, Sameer Agnihotri, Gary Kohanbash, Antony Michealraj, Ian Pollack, Baoli Hu. SMARCD3-regulated Purkinje cell migration underlies cerebellar development and group 3 medulloblastoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 629.