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.
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Gene Expression Omnibus
We thank R. D. Corbett, P. Plettner, N. Khuu and G. Edin for technical advice, the SickKids-UHN Flow Cytometry Facility for assistance with fluorescence-activated cell sorting, SickKids Laboratory Animal Services for animal housing and veterinary support, and The Centre for Applied Genomics, Princess Margaret Genomics Centre, and Canada’s Michael Smith Genome Sciences Centre for sequencing and bioinformatics support. This study was supported by the Canadian Institutes of Health Research (funding reference number 142434), the Ontario Institute for Cancer Research through funding provided by the Government of Ontario, and Stand Up To Cancer (SU2C) Canada. P.B.D. is also supported by the Terry Fox Research Institute, the Canadian Cancer Society, the Hospital for Sick Children Foundation, Jessica’s Footprint Foundation, the Hopeful Minds Foundation, the Bresler family, and B.R.A.I.N. Child. P.B.D. holds a Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children. B.D.S. acknowledges the support of the Wellcome Trust (grant number 098357/Z/12/Z). C.J.E. acknowledges grant support from the Canadian Cancer Society and the Terry Fox Run. Research was supported by SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up To Cancer Canada is a program of the Entertainment Industry Foundation Canada. Research funding is administered by the American Association for Cancer Research International – Canada, the scientific partner of SU2C Canada. The Structural Genomics Consortium is funded by AbbVie, Bayer, Boehringer Ingelheim, GSK, Genome Canada, Ontario Genomics Institute, Janssen, Lilly, Merck, Novartis, the government of Ontario, Pfizer, Takeda, and the Wellcome Trust.
Extended data figures
This file contains the normalized clone size quantification of barcoded xenografts for the GBM-719, -729, -735, -742, -743, and -754 series. The data is related to Figure 2 and Extended Data Figures 4-6.
This file contains clone growth trajectories derived from an instance of the stochastic simulation algorithm, as well as the change in mean clone size over time. The data is represented graphically in Figure 2d and Figure S1 in the Supplementary Theory.
This file contains the experimental and simulated clone survival probability values for the GBM-719, -742, and -754 series. The data is related to Figure 2g and Figure S2 in the Supplementary Theory.
This file contains the experimental and simulated clone size cross correlation values for the GBM-719, -742, and -754 series. The data is related to Figure 2f and Figure S3 in the Supplementary Theory.
This file contains the first incomplete moment distribution obtained from the stochastic simulation algorithm with random induction times. The data is related to Figure S4 in the Supplementary Theory.
This file contains the normalized clone size quantification for the proliferation assay from (1)754 culture. The data is related to Extended Data Figure 7d-f.
This file contains the normalized clone size quantification for the additional xenograft-derived cultures. The data is related to Extended Data Figure 8.
This file contains the normalized clone size quantification for the drug screen using (1)754 culture. The data is related to Figure 3g, Extended Data Figure 9c-d and Extended Data Figure 10.
About this article
NeuroMolecular Medicine (2018)