小柯机器人

美国约翰霍普金斯大学Konstantinos Konstantopoulos团队近期取得重要工作进展，他们研究发现细胞外液粘度升高会增强细胞迁移和癌细胞扩散。相关论文2022年11月2日在线发表于《自然》杂志上。

研究人员证明了粘度升高会反过来增加各种类型细胞在二维表面和封闭状态下的运动能力，并增加三维肿瘤球状体的细胞扩散。粘度升高带来的机械负荷增加诱发肌动蛋白2/3（ARP2/3）复合物依赖的致密肌动蛋白网络，它通过其肌动蛋白结合伴侣ezrin增强Na⁺/H⁺交换器1（NHE1）的极化。NHE1促进细胞膨胀和膜张力增加，进而激活瞬时受体电位阳离子香草素4（TRPV4）并介导钙流入，导致RHOA依赖的细胞收缩力增加。

肌动蛋白重塑及动态变化、NHE1介导的肿胀和基于RHOA收缩力的协调作用促进了在高粘度下运动能力的增强。预先暴露在高粘度环境中的乳腺癌细胞通过Hippo途径的转录控制获得TRPV4依赖性机械记忆，导致斑马鱼迁移增加，小鸡胚胎的外渗和小鼠的肺部定植。总的来说，细胞外黏度是调节短期和长期细胞过程的物理线索，与癌症生物学的病理生理学相关。

据介绍，细胞对物理刺激（如刚度、流体剪切应力和液压）会作出反应。细胞外液黏度在生理和病理条件下会发生变化（如癌症），这是一个关键的理线索。然而，粘度对癌症生物学的影响以及细胞应对黏度变化的感知和反应机制尚不清楚。

附：英文原文

Title: Extracellular fluid viscosity enhances cell migration and cancer dissemination

Author: Bera, Kaustav, Kiepas, Alexander, Godet, Ins, Li, Yizeng, Mehta, Pranav, Ifemembi, Brent, Paul, Colin D., Sen, Anindya, Serra, Selma A., Stoletov, Konstantin, Tao, Jiaxiang, Shatkin, Gabriel, Lee, Se Jong, Zhang, Yuqi, Boen, Adrianna, Mistriotis, Panagiotis, Gilkes, Daniele M., Lewis, John D., Fan, Chen-Ming, Feinberg, Andrew P., Valverde, Miguel A., Sun, Sean X., Konstantopoulos, Konstantinos

Issue&Volume: 2022-11-02

Abstract: Cells respond to physical stimuli, such as stiffness1, fluid shear stress2 and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.

DOI: 10.1038/s41586-022-05394-6

Source: https://www.nature.com/articles/s41586-022-05394-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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