ASCL1 directs the neuronal fate of neoplastic cells in glioblastoma

Tumours represent aberrant organogenesis with growth caused by unlimited proliferation and failure of differentiation of malignant precursor cells. I propose that defects in lineage commitment lock neoplastic cells in a self-renewing state that fuels tumour growth and treatment resistance. Thus, promoting terminal differentiation would limit clonal expansion and attenuate tumour growth. Herein, I identified that a substantial subset of patient-derived glioblastoma stem-like cells (GSCs) express ASCL1 (ASCL1hi GSCs), a proneural transcription factor involved in the generation of differentiated neurons during development and adult neurogenesis. In contrast to low expressing (ASCL1lo) GSCs, ASCL1hi GSCs are competent to undergo neuronal differentiation. The balance between self-renewal and differentiation in ASCL1hi GSCs is governed by Notch signaling, which can be manipulated with small molecules. Blocking Notch signaling in ASCL1hi GSCs increases levels of ASCL1, and leads to loss of self-renewal with neuronal commitment. Critically, even in a neoplastic context, enforced ASCL1 expression in ASCL1lo GSCs rescues neuronal differentiation competency, promotes terminal commitment, and attenuates tumourigenicity in vivo. Induction of ASCL1 results in new sites of open chromatin promoting expression of neuronal target genes, suggesting it functions as a pioneer factor to reorganize the chromatin enabling neuronal differentiation in the neoplastic context.Ph.D