Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Cell Stem Cell. 2017 Aug 3;21(2):209-224.e7. doi: 10.1016/j.stem.2017.06.004. Epub 2017 Jul 14.
Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1 GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1 GSCs do not. Increasing ASCL1 levels in ASCL1 GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.
神经胶质瘤表现出一种层次化的细胞组织，表明它们是由具有部分但异常分化潜能的肿瘤干细胞驱动的。在这里，我们表明，一大类患者来源的神经胶质瘤干细胞（GSCs）表达高水平的同源物 1（ASCL1），这是一种参与正常神经发生的神经前转录因子。ASCL1 GSCs 在 Notch 信号通路抑制下表现出潜在的终末神经元分化能力，而 ASCL1 GSCs 则没有。在 ASCL1 GSCs 中增加 ASCL1 水平可恢复神经元谱系潜能，促进终末分化，并降低致瘤性。ASCL1 通过在封闭染色质中作为先驱因子发挥作用，打开新的位点来激活神经发生基因表达程序，从而介导这些效应。将 GSCs 定向分化为终末细胞可能为 GBM 患者的亚组提供治疗应用，并强烈支持恢复 GBM 和其他癌症分化潜能的努力。
