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

Yonghe Wu,Michael Fletcher,Jörg Felsberg,Anna Bertoni,Zuguang Gu,Wei Wang,Ann Christin Gaupel ,Haikun Liu,Magdalena Schlotter,Ka Hou Man ,Peter Angel,Roland Eils,Tobias Weiss,Martje Barbus,Jasmin Mangei,Andrey Korshunov,Michael Weller,Peter Lichter,Carl Herrmann,Bárbara Costa ,Qi Wang,Guido Reifenberger,Bernhard Radlwimmer

doi:10.1038/s41467-020-20225-w

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.

Highlights

Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis
In this study, using chromatin and transcriptome gene regulatory network analyses, we show that glioblastoma subtypes have distinct enhancer landscapes and Master Regulator (MR) repertoires
In patient-derived and adherent cell line models, we found that SOX10 is an RTK I MR, and that its repression results in a transcriptomic and phenotypic RTK I-to-MES transition via remodelling of the enhancer landscape

Summary

Introduction

Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. The MES, RTK I and RTK II subtypes correspond to the mesenchymal, proneural and classical RNA expression subtypes[4], which were recently refined based on the analysis of exclusively IDH wildtype glioblastoma[5] Transitions between these subtypes have been observed during the treatment of patients[9,10] and may lead to worse prognosis[5,9]. We further show, using a recently described immunocompetent syngeneic mouse model that SOX10 loss leads to a dramatic decrease in survival, increased tumour invasion and immune cell infiltration These results show that GB subtype transitions can have striking effects on clinically relevant tumour phenotypes and, as such, require further investigation

Methods

Results

Conclusion