ASCL1 Promotes Differentiation of Glioblastoma Stem Cells

Glioblastoma is driven by a subpopulation of glioblastoma stem cells (GSC) with enhanced tumor propagating potential. Thus, therapeutic strategies to promote GSC differentiation may potentially suppress tumorigenesis. Notch signaling is responsible for maintaining neural stem cells and inhibiting neuronal differentiation by suppressing target genes including the proneural transcription factor Achaete-scute homolog 1 (ASCL1). Park and colleagues found that ASCL1 has higher relative expression in a subset of differentiation-competent GSCs. ASCL1 was expressed in a binary pattern with 35 primary glioblastoma-derived GSC cultures segregating into an ASCL1^hi and an ASCL1^lo subpopulation. The ASCL1^hi population was sensitive to Notch signaling disruption with a gamma-secretase inhibitor (GSI), exhibiting reduced sphere-forming ability, whereas the ASCL1^lo population was unaffected. Further, ASCL1 was required for neuronal differentiation in response to GSI treatment, and induction of ASCL1 expression in ASCL1^lo GSC cultures was sufficient to induce neuronal differentiation. In vivo, intracranial transplantation of ASCL1^lo GSCs resulted in tumor growth that was suppressed by the induction of ASCL1 overexpression, thereby extending survival. RNA-sequencing of ASCL1 wild-type and knockout GSCs after GSI treatment revealed that ASCL1 upregulates neurogenic program genes including TNR, MAP2, DLX2, and DCX, and similar ASCL1 targets were identified by ASCL1 induction in knockout cells. Mechanistically, ASCL1 acted as a pioneer factor, binding to closed chromatin at promoters and enhancers of neuronal target genes to facilitate chromatin opening and target gene expression. In addition to demonstrating that ASCL1 promotes neuronal differentiation of GSCs to suppress tumor growth, these findings suggest the possibility for therapies that induce GSC differentiation, such as Notch inhibitors, in glioblastoma patients with ASCL1^hi GSCs.

Park NI, Guilhamon P, Desai K, McAdam RF, Langille E, O'Connor M, et al. ASCL1 reorganizes chromatin to direct neuronal fate and suppress tumorigenicity of glioblastoma stem cells. Cell Stem Cell 2017;21:209–24.e7.

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