生物钟调节因子 CLOCK 促进胶质母细胞瘤的肿瘤血管生成。
Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma.
机构信息
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
出版信息
Cell Rep. 2023 Feb 28;42(2):112127. doi: 10.1016/j.celrep.2023.112127. Epub 2023 Feb 14.
Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hallmark, as a potential basis underlying CLOCK's pro-tumor effect in GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results in hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN). As a result, secreted POSTN promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. In GBM mouse and patient-derived xenograft models, blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis. Thus, the CLOCK-POSTN-TBK1 circuit coordinates a key tumor-endothelial cell interaction and represents an actionable therapeutic target for GBM.
胶质母细胞瘤（GBM）是成人中枢神经系统中最具侵袭性的肿瘤之一。我们之前的研究表明，神经胶质瘤干细胞（GSCs）的昼夜节律调节以旁分泌和自分泌的方式影响 GBM 的免疫抑制和 GSC 维持特征。在这里，我们扩展了涉及血管生成的机制，这是 GBM 的另一个关键特征，作为 CLOCK 在 GBM 中促进肿瘤的潜在基础。从机制上讲，CLOCK 指导的嗅觉素样 3（OLFML3）表达导致缺氧诱导因子 1-α（HIF1α）介导的骨膜蛋白（POSTN）转录上调。结果，分泌的 POSTN 通过激活内皮细胞中的 TANK 结合激酶 1（TBK1）信号促进肿瘤血管生成。在 GBM 小鼠和患者来源的异种移植模型中，阻断 CLOCK 指导的 POSTN-TBK1 轴可抑制肿瘤进展和血管生成。因此，CLOCK-POSTN-TBK1 回路协调了一个关键的肿瘤-内皮细胞相互作用，代表了 GBM 的一个可治疗的治疗靶点。
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