Glioblastoma stem cells respond to differentiation cues but fail to undergo commitment and terminal cell cycle arrest
Stem Cell Reports
Elsevier (Cell Press)
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Carén, H., Stricker, S., Bulstrode, H., Gagrica, S., Johnstone, E., Bartlett, T., Feber, A., et al. (2015). Glioblastoma stem cells respond to differentiation cues but fail to undergo commitment and terminal cell cycle arrest. Stem Cell Reports, 5 (5), 829-842. https://doi.org/10.1016/j.stemcr.2015.09.014
Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stemcell-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.
This work was supported by grants from The Brain Tumour Charity (grant 8/105) and Cancer Research UK (A9160). H.C. was supported by the Swedish Research Council and the Wenner-Gren foundation. P.B. was supported by EMBL and Biotechnology and Biological Sciences Research Council (BBSRC). Research in the S.B. lab was supported by Wellcome Trust (WT093855), Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510). S.M.P. was supported by a Wellcome Beit Memorial research fellowship, an Alex Bolt Research fellowship, and the Cancer Research UK Senior Research Fellowship (C25858/A19778).
External DOI: https://doi.org/10.1016/j.stemcr.2015.09.014
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273604
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Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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