Fluid shear stress activates YAP1 to promote cancer cell motility.
Fluid shear stress activates YAP1 to promote cancer cell motility.
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流体剪切应力激活YAP1以促进癌细胞的运动。
DOI：
10.1038/ncomms14122
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发表时间：
2017-01-18
影响因子：
16.6
通讯作者：
Wenzel PL
中科院分区：
文献类型：
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作者：
Lee HJ;Diaz MF;Price KM;Ozuna JA;Zhang S;Sevick-Muraca EM;Hagan JP;Wenzel PL
机械应力在恶性肿瘤的出口途径中普遍存在，但力对肿瘤细胞的内在影响仍知之甚少。在这里，我们证明淋巴管流动的摩擦力特征刺激 YAP1 驱动癌细胞迁移；而静脉或动脉血流典型的流体壁剪切应力（WSS）强度会抑制滑行。 WSS 增强的细胞运动严格需要 YAP1（而非 TAZ），因为阻断 YAP1、TEAD1-4 或 YAP1-TEAD 相互作用可将细胞速度降低至无流动时观察到的水平。 TEAD 的沉默导致 YAP1 的表型丧失，暗示转录反式激活功能在介导力增强的细胞迁移中。 WSS 决定 YAP1 效应子网络的表达，在 ROCK-LIMK-cofilin 信号轴下游的侵袭、趋化性和粘附中发挥执行作用。总而言之，这些数据表明 YAP1 作为一种流体机械传感器，其功能是调节促进转移的基因。癌细胞周围的流体摩擦力影响趋化因子的产生和化疗药物的输送，但尚不清楚它们是否通过生物力学效应直接影响肿瘤生物学。在这里，作者表明壁剪切应力刺激癌细胞通过 ROCK-LIMK-YAP 轴迁移。
Mechanical stress is pervasive in egress routes of malignancy, yet the intrinsic effects of force on tumour cells remain poorly understood. Here, we demonstrate that frictional force characteristic of flow in the lymphatics stimulates YAP1 to drive cancer cell migration; whereas intensities of fluid wall shear stress (WSS) typical of venous or arterial flow inhibit taxis. YAP1, but not TAZ, is strictly required for WSS-enhanced cell movement, as blockade of YAP1, TEAD1-4 or the YAP1–TEAD interaction reduces cellular velocity to levels observed without flow. Silencing of TEAD phenocopies loss of YAP1, implicating transcriptional transactivation function in mediating force-enhanced cell migration. WSS dictates expression of a network of YAP1 effectors with executive roles in invasion, chemotaxis and adhesion downstream of the ROCK–LIMK–cofilin signalling axis. Altogether, these data implicate YAP1 as a fluid mechanosensor that functions to regulate genes that promote metastasis. Fluid frictional forces around cancer cells influence chemokine production and delivery of chemotherapeutic drugs but it is unclear if they directly impact tumour biology through biomechanical effects. Here, the authors show that wall shear stress stimulates cancer cell migration through a ROCK–LIMK–YAP axis.