Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
Cell. 2011 Jul 8;146(1):148-63. doi: 10.1016/j.cell.2011.05.040.
Mechanotransduction is a key determinant of tissue homeostasis and tumor progression. It is driven by intercellular adhesions, cell contractility, and forces generated within the microenvironment and is dependent on extracellular matrix composition, organization, and compliance. We show that caveolin-1 (Cav1) favors cell elongation in three-dimensional cultures and promotes Rho- and force-dependent contraction, matrix alignment, and microenvironment stiffening through regulation of p190RhoGAP. In turn, microenvironment remodeling by Cav1 fibroblasts forces cell elongation. Cav1-deficient mice have disorganized stromal tissue architecture. Stroma associated with human carcinomas and melanoma metastases is enriched in Cav1-expressing carcinoma-associated fibroblasts (CAFs). Cav1 expression in breast CAFs correlates with low survival, and Cav1 depletion in CAFs decreases CAF contractility. Consistently, fibroblast expression of Cav1, through p190RhoGAP regulation, favors directional migration and invasiveness of carcinoma cells in vitro. In vivo, stromal Cav1 remodels peri- and intratumoral microenvironments to facilitate tumor invasion, correlating with increased metastatic potency. Thus, Cav1 modulates tissue responses through force-dependent architectural regulation of the microenvironment.
机械转导是组织动态平衡和肿瘤进展的关键决定因素。它由细胞间黏附、细胞收缩力以及微环境中产生的力驱动，并依赖于细胞外基质的组成、组织和顺应性。我们发现窖蛋白-1（Cav1）在三维培养中有利于细胞伸长，并通过调节 p190RhoGAP 促进 Rho 和力依赖性收缩、基质排列和微环境变硬。反过来，Cav1 成纤维细胞重塑微环境会迫使细胞伸长。缺乏 Cav1 的小鼠的基质组织结构紊乱。与人类癌和黑色素瘤转移相关的基质富含表达 Cav1 的癌相关成纤维细胞（CAF）。乳腺癌中的 CAF 表达 Cav1 与低生存率相关，而 CAF 中 Cav1 的耗竭会降低 CAF 的收缩性。一致地，通过 p190RhoGAP 调节，成纤维细胞中 Cav1 的表达有利于体外癌细胞的定向迁移和侵袭。在体内，基质 Cav1 重塑肿瘤周围和肿瘤内的微环境，以促进肿瘤侵袭，与转移能力增加相关。因此，Cav1 通过对微环境的力依赖性结构调节来调节组织反应。
