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.

中文翻译：

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人胶质母细胞瘤的命运定位揭示干细胞的层次结构不变

人胶质母细胞瘤具有驱动肿瘤发生的胶质母细胞瘤干细胞亚群。然而，胶质母细胞瘤细胞之间肿瘤内功能异质性的起源仍然知之甚少。在这里，我们研究了异种移植后条形码化胶质母细胞瘤细胞的无性进化，以定义其个体的命运行为。独立于不断发展的突变特征，我们显示了胶质母细胞瘤克隆在体内的生长这与一个明显的中性过程一致，该过程涉及根源于胶质母细胞瘤干细胞的保守的增殖体系。在这种模型中，慢循环的干细胞样细胞产生具有更广泛自我维持能力的循环较快的祖细胞群，进而产生非增殖性细胞。我们还确定了偏离这些动态的稀有“异常”克隆，并进一步表明化学疗法可促进已有的耐药性胶质母细胞瘤干细胞的扩增。最后，我们显示可以使用表观遗传化合物分别靶向功能不同的胶质母细胞瘤干细胞，这为胶质母细胞瘤靶向治疗提供了新途径。