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

Yonghe Wu, Michael Fletcher, Zuguang Gu, Qi Wang, Barbara Costa, Anna Bertoni, Ka-Hou Man, Magdalena Schlotter, Jörg Felsberg, Jasmin Mangei, Martje Barbus, Ann-Christin Gaupel, Wei Wang, Tobias Weiss, Roland Eils, Michael Weller, Haikun Liu, Guido Reifenberger, Andrey Korshunov, Peter Angel, Peter Lichter, Carl Herrmann () and Bernhard Radlwimmer ()
Additional contact information
Yonghe Wu: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Michael Fletcher: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Zuguang Gu: Heidelberg Center for Personalized Oncology (DKFZ-HIPO)
Qi Wang: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ)
Barbara Costa: Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance
Anna Bertoni: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Ka-Hou Man: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Magdalena Schlotter: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Jörg Felsberg: Heinrich Heine University
Jasmin Mangei: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Martje Barbus: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Ann-Christin Gaupel: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Wei Wang: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Tobias Weiss: University Hospital Zurich
Roland Eils: Heidelberg Center for Personalized Oncology (DKFZ-HIPO)
Michael Weller: University Hospital Zurich
Haikun Liu: Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance
Guido Reifenberger: Heinrich Heine University
Andrey Korshunov: University of Heidelberg
Peter Angel: Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance
Peter Lichter: Division of Molecular Genetics, German Cancer Research Center (DKFZ)
Carl Herrmann: Health Data Science Unit, Medical Faculty Heidelberg
Bernhard Radlwimmer: Division of Molecular Genetics, German Cancer Research Center (DKFZ)

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20225-w

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