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Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy

Author

Listed:
  • Xiaoyang Lan

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto)

  • David J. Jörg

    (Cavendish Laboratory, J. J. Thomson Avenue
    The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge)

  • Florence M. G. Cavalli

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Laura M. Richards

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto)

  • Long V. Nguyen

    (Terry Fox Laboratory, BC Cancer Agency)

  • Robert J. Vanner

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto)

  • Paul Guilhamon

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

  • Lilian Lee

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Michelle M. Kushida

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Davide Pellacani

    (Terry Fox Laboratory, BC Cancer Agency
    University of British Columbia)

  • Nicole I. Park

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto)

  • Fiona J. Coutinho

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto)

  • Heather Whetstone

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Hayden J. Selvadurai

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Clare Che

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Betty Luu

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Annaick Carles

    (Centre for High-Throughput Biology, University of British Columbia)

  • Michelle Moksa

    (Centre for High-Throughput Biology, University of British Columbia)

  • Naghmeh Rastegar

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Renee Head

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children)

  • Sonam Dolma

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto)

  • Panagiotis Prinos

    (University of Toronto
    Structural Genomics Consortium, University of Toronto)

  • Michael D. Cusimano

    (St. Michael’s Hospital
    University of Toronto)

  • Sunit Das

    (St. Michael’s Hospital
    University of Toronto)

  • Mark Bernstein

    (University of Toronto
    Toronto Western Hospital)

  • Cheryl H. Arrowsmith

    (University of Toronto
    Structural Genomics Consortium, University of Toronto)

  • Andrew J. Mungall

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Richard A. Moore

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Yussanne Ma

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Marco Gallo

    (Biochemistry and Molecular Biology, Alberta Children’s Hospital Research Institute, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary)

  • Mathieu Lupien

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

  • Trevor J. Pugh

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto)

  • Michael D. Taylor

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto
    University of Toronto)

  • Martin Hirst

    (Centre for High-Throughput Biology, University of British Columbia
    Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Connie J. Eaves

    (Terry Fox Laboratory, BC Cancer Agency
    University of British Columbia)

  • Benjamin D. Simons

    (Cavendish Laboratory, J. J. Thomson Avenue
    The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge
    The Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge)

  • Peter B. Dirks

    (Developmental and Stem Cell Biology Program, The Hospital for Sick Children
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
    University of Toronto
    University of Toronto)

Abstract

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare ‘outlier’ clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

Suggested Citation

  • Xiaoyang Lan & David J. Jörg & Florence M. G. Cavalli & Laura M. Richards & Long V. Nguyen & Robert J. Vanner & Paul Guilhamon & Lilian Lee & Michelle M. Kushida & Davide Pellacani & Nicole I. Park & , 2017. "Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy," Nature, Nature, vol. 549(7671), pages 227-232, September.
  • Handle: RePEc:nat:nature:v:549:y:2017:i:7671:d:10.1038_nature23666
    DOI: 10.1038/nature23666
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    Citations

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    Cited by:

    1. Wei Cheng & Hao-Long Li & Shao-Yan Xi & Xiao-Feng Zhang & Yun Zhu & Le Xing & Yan-Xuan Mo & Mei-Mei Li & Fan-En Kong & Wen-Jie Zhu & Xiao-Gang Chen & Hui-Qing Cui & Zhi-Ming Cao & Yuan-Feng Gong & Yun, 2021. "Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Akram A. Hamed & Daniel J. Kunz & Ibrahim El-Hamamy & Quang M. Trinh & Omar D. Subedar & Laura M. Richards & Warren Foltz & Garrett Bullivant & Matthaeus Ware & Maria C. Vladoiu & Jiao Zhang & Antony , 2022. "A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Francesco Antonica & Lucia Santomaso & Davide Pernici & Linda Petrucci & Giuseppe Aiello & Alessandro Cutarelli & Luciano Conti & Alessandro Romanel & Evelina Miele & Toma Tebaldi & Luca Tiberi, 2022. "A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Claire Vinel & Gabriel Rosser & Loredana Guglielmi & Myrianni Constantinou & Nicola Pomella & Xinyu Zhang & James R. Boot & Tania A. Jones & Thomas O. Millner & Anaelle A. Dumas & Vardhman Rakyan & Je, 2021. "Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    5. Yan Zhang & Chi Yan Wong & Carine Z. J. Lim & Qingchang Chen & Zhonglang Yu & Auginia Natalia & Zhigang Wang & Qing You Pang & See Wee Lim & Tze Ping Loh & Beng Ti Ang & Carol Tang & Huilin Shao, 2023. "Multiplexed RNA profiling by regenerative catalysis enables blood-based subtyping of brain tumors," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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