eLife (Jan 2021)
Single-cell chromatin accessibility profiling of glioblastoma identifies an invasive cancer stem cell population associated with lower survival
- Paul Guilhamon,
- Charles Chesnelong,
- Michelle M Kushida,
- Ana Nikolic,
- Divya Singhal,
- Graham MacLeod,
- Seyed Ali Madani Tonekaboni,
- Florence MG Cavalli,
- Christopher Arlidge,
- Nishani Rajakulendran,
- Naghmeh Rastegar,
- Xiaoguang Hao,
- Rozina Hassam,
- Laura J Smith,
- Heather Whetstone,
- Fiona J Coutinho,
- Bettina Nadorp,
- Katrina I Ellestad,
- H Artee Luchman,
- Jennifer Ai-wen Chan,
- Molly S Shoichet,
- Michael D Taylor,
- Benjamin Haibe-Kains,
- Samuel Weiss,
- Stephane Angers,
- Marco Gallo,
- Peter B Dirks,
- Mathieu Lupien
Affiliations
- Paul Guilhamon
- ORCiD
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Charles Chesnelong
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Michelle M Kushida
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Ana Nikolic
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
- Divya Singhal
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
- Graham MacLeod
- ORCiD
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
- Seyed Ali Madani Tonekaboni
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Florence MG Cavalli
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Christopher Arlidge
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Nishani Rajakulendran
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
- Naghmeh Rastegar
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Xiaoguang Hao
- ORCiD
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Department of Cell Biology & Anatomy, University of Calgary, Calgary, Canada
- Rozina Hassam
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Department of Cell Biology & Anatomy, University of Calgary, Calgary, Canada
- Laura J Smith
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
- Heather Whetstone
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Fiona J Coutinho
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Bettina Nadorp
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Katrina I Ellestad
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
- H Artee Luchman
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Department of Cell Biology & Anatomy, University of Calgary, Calgary, Canada
- Jennifer Ai-wen Chan
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada
- Molly S Shoichet
- ORCiD
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
- Michael D Taylor
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada; Division of Neurosurgery, University of Toronto, Toronto, Canada; Departments of Molecular Genetics and Surgery, University of Toronto, Toronto, Canada
- Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Computer Science, University of Toronto, Toronto, Canada; Ontario Institute for Cancer Research, Toronto, Canada; Vector Institute, Toronto, Canada
- Samuel Weiss
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Department of Cell Biology & Anatomy, University of Calgary, Calgary, Canada; Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada
- Stephane Angers
- ORCiD
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada
- Marco Gallo
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada; Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada; Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada
- Peter B Dirks
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, Canada; Division of Neurosurgery, University of Toronto, Toronto, Canada; Ontario Institute for Cancer Research, Toronto, Canada
- Mathieu Lupien
- ORCiD
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada
- DOI
- https://doi.org/10.7554/eLife.64090
- Journal volume & issue
-
Vol. 10
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.
Keywords