EXTH-79. HIJACKING A NEURODEVELOPMENTAL EPIGENOMIC PROGRAM IN METASTATIC DISSEMINATION OF MEDULLOBLASTOMA

Abstract Normal brain development relies on precise genetic and epigenetic spatiotemporal regulation of gene expression. How dysregulation neurodevelopment relates to medulloblastoma, the most common pediatric tumor, remains elusive. Here, we uncovered a novel neurodevelopmental epigenomic program that regulates Purkinje cell migration in developing cerebellum is hijacked induce tumor metastatic dissemination medulloblastoma. Integrating publicly available datasets with our in-house data, unsupervised analyses revealed BAF60C/SMARCD3, subunit SWI/SNF chromatin remodeling complex, promotes vitro metastasis vivo. Based analyzing single-cell RNAseq data developmental trajectory mice humans, aligning medulloblastoma patients’ datasets, found BAF60C/SMARCD3 regulated DAB1-mediated Reelin signaling involved positioning during by orchestrating cis-regulatory elements (CREs) at DAB1 locus. Moreover, analysis expression architecture human mouse demonstrated transcription activity BAF60C/SMARCD3-DAB1 circuit downregulated mature state cerebellar development, however, upregulated We further identified core set factors, enhancer zeste homolog 2 (EZH2) nuclear factor I X (NFIX), bi-directionally control transcriptional coordinating CREs locus form hub dissemination. Highly expressed activates Reelin/DAB1 pathway downstream Src kinase, which was validated pair-wised primary tumors from patients. Preclinical models inhibiting reduces lower safe dose. Together, these deepen understanding how influences disease progression provide an opportunity for therapeutics this devastating cancer children.