Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
Seve-Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
Cancer Cell. 2017 Nov 13;32(5):590-607.e4. doi: 10.1016/j.ccell.2017.10.006.
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.
多形性胶质母细胞瘤（GBM）是一种致命且常见的脑肿瘤。高增殖和细胞异质性与不良预后相关，其中包括神经胶质瘤干细胞（GSCs）。端粒基因经常发生突变。端粒结合蛋白 TRF1 对于端粒保护以及成体和多能干细胞至关重要。在这里，我们发现 TRF1 在小鼠和人类 GBM 中上调。在 GBM 小鼠模型中，大脑特异性 Trf1 基因缺失抑制了 GBM 的起始和进展，提高了生存率。Trf1 缺失增加了端粒 DNA 损伤，并减少了增殖和干细胞特性。TRF1 化学抑制剂在人类 GBM 细胞中模拟了这些效应，并且还阻断了源自患者来源的原发性 GSCs 的异种移植物中的肿瘤球体形成和肿瘤生长。因此，通过抑制 TRF1 来靶向端粒是 GBM 的一种有效治疗策略。
