Summary
Mechanotransduction is a key determinant of tissue homeostasis and tumor progression. It is dri
ven by intercellular adhesions, cell contractility, and forces generated within the microen
vironment and is dependent on extracellular matrix composition, organization, and compliance. We show that ca
veolin-1 (Ca
v1) fa
vors cell elongation in three-dimensional cultures and promotes Rho- and force-dependent contraction, matrix alignment, and microen
vironment stiffening through regulation of p190RhoGAP. In turn, microen
vironment remodeling by Ca
v1 fibroblasts forces cell elongation. Ca
v1-deficient mice ha
ve disorganized stromal tissue architecture. Stroma associated with human carcinomas and melanoma metastases is enriched in Ca
v1-expressing carcinoma-associated fibroblasts (CAFs). Ca
v1 expression in breast CAFs correlates with low sur
vi
val, and Ca
v1 depletion in CAFs decreases CAF contractility. Consistently, fibroblast expression of Ca
v1, through p190RhoGAP regulation, fa
vors directional migration and in
vasi
veness of carcinoma cells in
vitro. In
vi
vo, stromal Ca
v1 remodels peri- and intratumoral microen
vironments to facilitate tumor in
vasion, correlating with increased metastatic potency. Thus, Ca
v1 modulates tissue responses through force-dependent architectural regulation of the microen
vironment.
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