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Nature. 2017 Sep 14;549(7671):227-232. doi: 10.1038/nature23666. Epub 2017 Aug 30.

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy.

Lan X1,2,3, Jörg DJ4,5, Cavalli FMG1,2, Richards LM6,7, Nguyen LV8, Vanner RJ1,2,3, Guilhamon P6,7,9, Lee L1,2, Kushida MM1,2, Pellacani D8,10, Park NI1,2,3, Coutinho FJ1,2,3, Whetstone H1,2, Selvadurai HJ1,2, Che C1,2, Luu B1,2, Carles A11, Moksa M11, Rastegar N1,2, Head R1,2, Dolma S1,2,12, Prinos P7,13, Cusimano MD14,15, Das S14,15, Bernstein M15,16, Arrowsmith CH7,13, Mungall AJ17, Moore RA17, Ma Y17, Gallo M18, Lupien M6,7,9, Pugh TJ6,7, Taylor MD1,2,12,15,19, Hirst M11,17, Eaves CJ8,10, Simons BD4,5,20, Dirks PB1,2,3,12,15,19.

Author information

1
Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
2
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
3
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
4
Cavendish Laboratory, Department of Physics, J. J. Thomson Avenue, Cambridge CB3 0HE, UK.
5
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
6
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
7
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
8
Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
9
Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
10
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
11
Centre for High-Throughput Biology, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
12
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
13
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
14
Division of Neurosurgery, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
15
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
16
Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada.
17
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
18
Departments of Physiology and Pharmacology, Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
19
Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
20
The Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.

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.

PMID:
28854171
PMCID:
PMC5608080
DOI:
10.1038/nature23666
[Indexed for MEDLINE]
Free PMC Article

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