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Stem Cell Reports. 2015 Nov 10;5(5):829-842. doi: 10.1016/j.stemcr.2015.09.014.

Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest.

Author information

1
Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; Samantha Dickson Brain Cancer Unit, University College London, London WC1E 6BT, UK.
2
Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Samantha Dickson Brain Cancer Unit, University College London, London WC1E 6BT, UK.
3
Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
4
Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
5
European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
6
Department of Mathematics and CoMPLEX, University College London, London WC1E 6BT, UK.
7
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Tennis Court Road, University of Cambridge, Cambridge CB2 1QR, UK; European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK; Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
8
Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. Electronic address: s.beck@ucl.ac.uk.
9
Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Samantha Dickson Brain Cancer Unit, University College London, London WC1E 6BT, UK; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh bioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK. Electronic address: steven.pollard@ed.ac.uk.

Abstract

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 stemcells (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. Herewe find only a subset ofGSCcultures 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 forGBM.

PMID:
26607953
PMCID:
PMC4649264
DOI:
10.1016/j.stemcr.2015.09.014
[Indexed for MEDLINE]
Free PMC Article

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