Single-cell chromatin accessibility profiling of glioblastoma identifies an invasive cancer stem cell population associated with lower survival

Author:

Guilhamon Paul12ORCID,Chesnelong Charles2,Kushida Michelle M2,Nikolic Ana345,Singhal Divya345,MacLeod Graham6ORCID,Madani Tonekaboni Seyed Ali17,Cavalli Florence MG2,Arlidge Christopher1,Rajakulendran Nishani6,Rastegar Naghmeh2,Hao Xiaoguang389ORCID,Hassam Rozina389,Smith Laura J10,Whetstone Heather2,Coutinho Fiona J2,Nadorp Bettina1,Ellestad Katrina I34,Luchman H Artee389,Chan Jennifer Ai-wen3411,Shoichet Molly S10ORCID,Taylor Michael D21213,Haibe-Kains Benjamin17141516,Weiss Samuel38917,Angers Stephane618ORCID,Gallo Marco34517,Dirks Peter B21215,Lupien Mathieu17ORCID

Affiliation:

1. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2. Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada

3. Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada

4. Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada

5. Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada

6. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada

7. Department of Medical Biophysics, University of Toronto, Toronto, Canada

8. Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

9. Department of Cell Biology & Anatomy, University of Calgary, Calgary, Canada

10. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada

11. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada

12. Division of Neurosurgery, University of Toronto, Toronto, Canada

13. Departments of Molecular Genetics and Surgery, University of Toronto, Toronto, Canada

14. Department of Computer Science, University of Toronto, Toronto, Canada

15. Ontario Institute for Cancer Research, Toronto, Canada

16. Vector Institute, Toronto, Canada

17. Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada

18. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada

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.

Funder

Stand Up To Cancer Canada, Genome Canada, CIHR, OICR, AACR

CIHR

Princess Margaret Cancer Foundation

Terry Fox Research Institute

Hospital for Sick Children

Canadian Cancer Society

NSERC

Alliance for Cancer Gene Therapy

Jessica's Footprint

Hopeful Minds

The Bresler Family

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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