Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.

Autor: Wu Y; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Fletcher M; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Gu Z; Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Wang Q; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Costa B; Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Bertoni A; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Man KH; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Schlotter M; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Felsberg J; Medical Faculty, Institute of Neuropathology, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.; German Cancer Consortium (DKTK), Partner site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Mangei J; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Barbus M; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Gaupel AC; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Wang W; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Weiss T; Department of Neurology and Brain Tumor Center, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091, Zurich, Switzerland., Eils R; Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Weller M; Department of Neurology and Brain Tumor Center, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091, Zurich, Switzerland., Liu H; Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Reifenberger G; Medical Faculty, Institute of Neuropathology, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.; German Cancer Consortium (DKTK), Partner site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Korshunov A; Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany.; Clinical Cooperation Unit, Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 220-221, 69120, Heidelberg, Germany., Angel P; Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Lichter P; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; German Cancer Consortium (DKTK), Partner site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Herrmann C; Health Data Science Unit, Medical Faculty Heidelberg, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany. carl.herrmann@bioquant.uni-heidelberg.de., Radlwimmer B; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. b.radlwimmer@dkfz.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Dec 18; Vol. 11 (1), pp. 6434. Date of Electronic Publication: 2020 Dec 18.
DOI: 10.1038/s41467-020-20225-w
Abstrakt: Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. Here, we perform multi-omic profiling of 60 glioblastoma primary tumours and use orthogonal analysis of chromatin and RNA-derived gene regulatory networks to identify 38 subtype master regulators, whose cell population-specific activities we further map in published single-cell RNA sequencing data. These analyses identify the oligodendrocyte precursor marker and chromatin modifier SOX10 as a master regulator in RTK I-subtype tumours. In vitro functional studies demonstrate that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. SOX10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects.
Databáze: MEDLINE
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