Glioblastoma stem cells respond to differentiation cues but fail to undergo commitment and terminal cell cycle arrest

Helena Caren, Stefan H Stricker, Harry Bulstrode, Sladjana Gagrica, Ewan Johnstone, Thomas Bartlett, Andrew Feber, Gareth Wilson, Andrew E Teschendorff, Paul Bertone, Stephan Beck, Steven M. Pollard

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stem cell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stem cells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Here we find only a subset of GSC cultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy for GBM.
Original languageEnglish
Pages (from-to)829–842
JournalStem Cell Reports
Volume5
Issue number5
Early online date22 Dec 2015
DOIs
Publication statusE-pub ahead of print - 22 Dec 2015

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