CNSC-46. GLIOBLASTOMA INITIATION, MIGRATION, AND CELL TYPES ARE REGULATED BY CORE BHLH TRANSCRIPTION FACTORS ASCL1 AND OLIG2

Abstract Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The neurodevelopmental transcription factors ASCL1 and OLIG2 are highly co-expressed in GBMs. However, their combinatorial roles in regulating the hierarchy and heterogeneity of GBM cells are unknown. Here, we show that induction of somatic mutations in neural progenitor cells lead to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other’s loci and to downstream target genes then determine the cell types and degree of migration of tumor cells. Notably, single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in promoting neural stem cell (NSC)/astrocyte-like tumor cell types, which are highly proliferative, migratory, and are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.