title: Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo  Commitment and Terminal Cell-Cycle Arrest.
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.
authors.affiliation: 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.
authors.forename: Helena
authors.initials: H
authors.lastname: Carén
authors.affiliation: 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.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Stricker
authors.affiliation: Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Harry
authors.initials: H
authors.lastname: Bulstrode
authors.affiliation: Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Gagrica
authors.affiliation: European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Johnstone
authors.affiliation: Department of Mathematics and CoMPLEX, University College London, London WC1E 6BT, UK.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Bartlett
authors.affiliation: Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Wilson
authors.affiliation: Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: 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.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D055747:SOX Transcription Factors / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D055747:SOX Transcription Factors