| Literature DB >> 28712938 |
Nicole I Park1, Paul Guilhamon2, Kinjal Desai3, Rochelle F McAdam1, Ellen Langille4, Madlen O'Connor3, Xiaoyang Lan1, Heather Whetstone3, Fiona J Coutinho1, Robert J Vanner1, Erick Ling5, Panagiotis Prinos6, Lilian Lee3, Hayden Selvadurai3, Gurnit Atwal4, Michelle Kushida3, Ian D Clarke7, Veronique Voisin8, Michael D Cusimano9, Mark Bernstein10, Sunit Das9, Gary Bader11, Cheryl H Arrowsmith12, Stephane Angers13, Xi Huang1, Mathieu Lupien14, Peter B Dirks15.
Abstract
Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.Entities:
Keywords: ASCL1; NOTCH; brain tumor; cancer stem cell; differentiation therapy; fate specification; glioblastoma; neuronal differentiation; pioneer transcription factor; self-renewal
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Year: 2017 PMID： 28712938 DOI： 10.1016/j.stem.2017.06.004
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633