Abstract
Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as Glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary human GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival, in line with the higher invasive properties of Invasive state GSCs compared to Reactive and Constructive GSCs as shown by in vitro and in vivo assays. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.
Data availability
The GSCs are available upon reasonable request from PBD and SW. The GSC ATAC-seq and DNA methylation data have been deposited at GEO (GSE109399). The scATAC-seq data has been deposited at GEO (GSE139136). RNA-seq data are available at EGA (EGAS00001003070).
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Epigenetic characterization of glioblastoma stem cellsNCBI Gene Expression Omnibus, GSE109399.
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Single-cell ATAC-Seq of Adult GBMNCBI Gene Expression Omnibus, GSE139136.
Article and author information
Author details
Funding
CIHR (TGH-158221)
- Stephane Angers
- Peter B Dirks
- Mathieu Lupien
SU2C canada (SU2C-AACR-DT-19-15)
- Michael D Taylor
- Sam Weiss
- Peter B Dirks
- Mathieu Lupien
CIHR (MFE 338954)
- Paul Guilhamon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were performed according to and approved by the Animal Care Committee of the Hospital for Sick Children or the University of Calgary. All attempts are made to minimize the handling time during surgery and treatment so as not to unduly stress the animals. Animals are observed daily after surgery to ensure there are no unexpected complications
Human subjects: All tissue samples were obtained following informed consent from patients, and all experimental procedures were performed in accordance with the Research Ethics Board at The Hospital for Sick Children (Toronto, Canada), the University of Calgary Ethics Review Board, and the Health Research Ethics Board of Alberta - Cancer Committee (HREBA). Approval to pathological data was obtained from the respective institutional review boards.
Reviewing Editor
- Lynne-Marie Postovit, University of Alberta, Canada
Publication history
- Received: October 17, 2020
- Accepted: January 8, 2021
- Accepted Manuscript published: January 11, 2021 (version 1)
- Version of Record published: January 29, 2021 (version 2)
Copyright
© 2021, Guilhamon et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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