CNSC-93. SMARCD3 REGULATING THE REELIN PATHWAY TO ADJUST PURKINJE CELL MIGRATION AND MEDULLOBLASTOMA METASTASIS

Abstract Medulloblastoma (MB) is a fast-growing and heterogeneous brain tumor arising in the cerebellum. Group 3, one of four MB subgroups (WNT, SHH, Group 3, and Group 4), is the most aggressive and malignant type in children. 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. Furthermore, elevated SMARCD3 expression is associated with patient poor outcomes, MB metastatic phenotype, and activation of the Reelin signaling pathway that is required for PC migration and positioning in cerebellar development. Conditional Smarcd3 knockout in PCs results in early death in mice, and the surviving animals exhibit significantly impaired motor coordination and balance ability. Histological staining 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 all together 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 for MB metastatic dissemination. 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.