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Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy
Lan X, Jörg DJ, Cavalli FMG, Richards LM, Nguyen LV, Vanner RJ, Guilhamon P, Lee L, Kushida MM, Pellacani D, Park NI, Coutinho FJ, Whetstone H, Selvadurai HJ, Che C, Luu B, Carles A, Moksa M, Rastegar N, Head R, Dolma S, Prinos P, Cusimano MD, Das S, Bernstein M, Arrowsmith CH, Mungall AJ, Moore RA, Ma Y, Gallo M, Lupien M, Pugh TJ, Taylor MD, Hirst M, Eaves CJ, Simons BD, Dirks PB. Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. Nature. 2017 Aug 30. doi: 10.1038/nature23666. [Epub ahead of print]
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.
Co-author Connie Eaves of the B.C. Cancer Agency, who focuses on stem cell research related to leukemia and breast cancer, said barcoding has been used in studying other cancers, “but this is one of the first times that a method has been used to individually track the cells that propagate tumours and respond to different types of therapies.”