Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK.
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
Nat Commun. 2021 Apr 12;12(1):2184. doi: 10.1038/s41467-021-22225-w.
Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
胶质母细胞瘤是由具有部分分化潜能的神经胶质瘤干细胞驱动的具有层次结构的肿瘤。神经胶质瘤干细胞存在于专门的微环境中，但它们是否以及如何在这些龛外进行谱系进展仍不清楚。在这里，我们确定了白质是具有少突胶质细胞谱系能力的胶质母细胞瘤的分化龛。与白质接触的肿瘤细胞获得少突前体细胞命运，导致增殖和侵袭减少。分化是对白质损伤的反应，这是肿瘤浸润本身在肿瘤抑制反馈环中引起的。从机制上讲，肿瘤细胞分化是由 SOX10 的选择性白质上调驱动的，SOX10 是正常少突胶质细胞发生的主要调节因子。SOX10 的过表达或用促进髓鞘形成的药物治疗，上调内源性 SOX10，模拟这种反应，导致无龛依赖性少突前体细胞分化和体内肿瘤抑制。因此，胶质母细胞瘤再现了一种损伤反应，利用这种潜在的程序可能为一部分患者提供治疗机会。
