Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy

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, Fiona J. Coutinho, Heather Whetstone, Hayden J. Selvadurai, Clare Che, Betty Luu, Annaick Carles, Michelle Moksa, Naghmeh Rastegar, Renee Head, Sonam Dolma, Panagiotis Prinos, Michael D. Cusimano, Sunit Das, Mark Bernstein, Cheryl H. Arrowsmith, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Marco Gallo, Mathieu Lupien, Trevor J. Pugh, Michael D. Taylor, Martin Hirst, Connie J. Eaves, Benjamin D. Simons () and Peter B. Dirks ()
Additional contact information
Xiaoyang Lan: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
David J. Jörg: Cavendish Laboratory, J. J. Thomson Avenue
Florence M. G. Cavalli: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Laura M. Richards: Princess Margaret Cancer Centre, University Health Network
Long V. Nguyen: Terry Fox Laboratory, BC Cancer Agency
Robert J. Vanner: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Paul Guilhamon: Princess Margaret Cancer Centre, University Health Network
Lilian Lee: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Michelle M. Kushida: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Davide Pellacani: Terry Fox Laboratory, BC Cancer Agency
Nicole I. Park: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Fiona J. Coutinho: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Heather Whetstone: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Hayden J. Selvadurai: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Clare Che: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Betty Luu: Developmental and Stem Cell Biology Program, 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
Renee Head: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Sonam Dolma: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Panagiotis Prinos: University of Toronto
Michael D. Cusimano: St. Michael’s Hospital
Sunit Das: St. Michael’s Hospital
Mark Bernstein: University of Toronto
Cheryl H. Arrowsmith: 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
Trevor J. Pugh: Princess Margaret Cancer Centre, University Health Network
Michael D. Taylor: Developmental and Stem Cell Biology Program, The Hospital for Sick Children
Martin Hirst: Centre for High-Throughput Biology, University of British Columbia
Connie J. Eaves: Terry Fox Laboratory, BC Cancer Agency
Benjamin D. Simons: Cavendish Laboratory, J. J. Thomson Avenue
Peter B. Dirks: Developmental and Stem Cell Biology Program, The Hospital for Sick Children

Nature, 2017, vol. 549, issue 7671, 227-232

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature23666

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