Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.
Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.
复制标题
DOI：
10.1038/ncb3429
复制
发表时间：
2016-12
影响因子：
21.3
通讯作者：
Weaver VM
中科院分区：
文献类型：
--
作者：
Miroshnikova YA;Mouw JK;Barnes JM;Pickup MW;Lakins JN;Kim Y;Lobo K;Persson AI;Reis GF;McKnight TR;Holland EC;Phillips JJ;Weaver VM
神经胶质瘤脑肿瘤患者总体生存率的提高与代谢调节剂异柠檬酸脱氢酶 1 (IDH1) 的突变有关。胶质瘤在机械挑战的微环境中发展，其特点是致密的细胞外基质 (ECM)，会损害血管完整性，从而诱导缺氧并激活 HIF1α。我们发现神经胶质瘤的侵袭性和患者预后与 HIF1α 水平和富含生腱蛋白 C (TNC) 的 ECM 的硬度相关。功能获得和丧失功能的异种移植操作表明，突变的 IDH1 通过减少 HIF1α 依赖性 TNC 表达来降低 ECM 硬度和机械信号传导，从而限制神经胶质瘤的侵袭。复发性 IDH1 突变患者神经胶质瘤具有更坚硬的富含 TNC 的 ECM，我们的研究将此归因于通过张力依赖性正反馈环介导的 miR-203 对 HIF1α 和 TNC 的抑制减少。因此，我们的工作表明，ECM 硬度升高可以独立促进胶质母细胞瘤的侵袭性，并通过绕过 IDH1 突变状态的保护活性，导致胶质母细胞瘤复发。
Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.