A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression
A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression
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由机械敏感离子通道 PIEZO1 和组织力学介导的前馈机制促进胶质瘤侵袭。
DOI：
10.1016/j.neuron.2018.09.046
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发表时间：
2018-11-21
期刊：
影响因子：
16.2
通讯作者：
Huang, Xi
中科院分区：
文献类型：
--
作者：
Chen, Xin;Wanggou, Siyi;Huang, Xi
组织力学特性的改变是包括胶质瘤在内的实体瘤的物理特征。肿瘤细胞如何感知和调节组织力学在很大程度上是未知的。在这里，我们发现机械敏感离子通道压电调节有丝分裂和组织硬度的果蝇胶质瘤，而不是非转化的大脑。PIEZO1在侵袭性胶质瘤中过表达，其表达与患者生存率呈负相关。删除PIEZO1可以抑制胶质母细胞瘤干细胞的生长，抑制肿瘤的发展，延长小鼠的生存期。局部机械力激活来自胶质瘤细胞过程的突出的piezo1依赖性电流，但不激活体细胞。PIEZO1定位于局灶粘连，激活整合素- fak信号，调节细胞外基质，增强组织硬化。反过来，更硬的机械微环境会提高PIEZO1的表达，从而促进胶质瘤的侵袭。因此，胶质瘤细胞以PIEZO1依赖的方式具有机械感觉，靶向PIEZO1代表了一种策略，可以打破肿瘤细胞机械传导和异常组织力学之间相互作用的、加重疾病的前馈回路。
Alteration of tissue mechanical properties is a physical hallmark of solid tumors including gliomas. How tumor cells sense and regulate tissue mechanics is largely unknown. Here, we show that mechanosensitive ion channel Piezo regulates mitosis and tissue stiffness of Drosophila gliomas, but not non-transformed brains. PIEZO1 is overexpressed in aggressive human gliomas and its expression inversely correlates with patient survival. Deleting PIEZO1 suppresses the growth of glioblastoma stem cells, inhibits tumor development, and prolongs mouse survival. Focal mechanical force activates prominent PIEZO1-dependent currents from glioma cell processes, but not soma. PIEZO1 localizes at focal adhesions to activate integrin-FAK signaling, regulate extracellular matrix, and reinforce tissue stiffening. In turn, a stiffer mechanical microenvironment elevates PIEZO1 expression to promote glioma aggression. Therefore, glioma cells are mechanosensory in a PIEZO1-dependent manner, and targeting PIEZO1 represents a strategy to break the reciprocal, disease-aggravating feedforward circuit between tumor cell mechanotransduction and the aberrant tissue mechanics.