ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells

Publication date: Available online 14 July 2017
Source:Cell Stem Cell
Author(s): Nicole I. Park, Paul Guilhamon, Kinjal Desai, Rochelle F. McAdam, Ellen Langille, Madlen O'Connor, Xiaoyang Lan, Heather Whetstone, Fiona J. Coutinho, Robert J. Vanner, Erick Ling, Panagiotis Prinos, Lilian Lee, Hayden Selvadurai, Gurnit Atwal, Michelle Kushida, Ian D. Clarke, Veronique Voisin, Michael D. Cusimano, Mark Bernstein, Sunit Das, Gary Bader, Cheryl H. Arrowsmith, Stephane Angers, Xi Huang, Mathieu Lupien, Peter B. Dirks
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. ASCL1^hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1^lo GSCs do not. Increasing ASCL1 levels in ASCL1^lo 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.

Graphical abstract

Teaser

Glioblastoma is characterized by a block in cellular differentiation. Park et al. identify a subset of glioblastoma stem cells (GSCs) that express high levels of the proneural transcription factor ASCL1 and differentiate in response to Notch inhibition, effectively abrogating their stemness properties and tumorigenic potential.


http://ift.tt/2tocZOK