Biomechanical Remodeling of the Microenvironment by Stromal Caveolin-1 Favors Tumor Invasion and Metastasis

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 caveoli...

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Bibliographic Details
Published in:Cell 2011-07, Vol.146 (1), p.148-163
Main Authors: Goetz, Jacky G., Minguet, Susana, Navarro-Lérida, Inmaculada, Lazcano, Juan José, Samaniego, Rafael, Calvo, Enrique, Tello, Marta, Osteso-Ibáñez, Teresa, Pellinen, Teijo, Echarri, Asier, Cerezo, Ana, Klein-Szanto, Andres J.P., Garcia, Ricardo, Keely, Patricia J., Sánchez-Mateos, Paloma, Cukierman, Edna, Del Pozo, Miguel A.
Format: Article
Language:English
Subjects:
Animals
biomechanics
carcinoma
Caveolin 1 - metabolism
cell elongation
cell growth
Cell Movement
compliance
extracellular matrix
fibroblasts
Fibroblasts - pathology
homeostasis
Humans
mechanotransduction
melanoma
Melanoma - pathology
metastasis
Mice
Mice, Knockout
neoplasm cells
Neoplasm Metastasis - pathology
Neoplasms - pathology
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Summary: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. [Display omitted] [Display omitted] ► Cav1 controls cell contractility and matrix remodeling through p190RhoGAP regulation ► Biomechanical remodeling by stromal Cav1 regulates tissue architecture ► Carcinoma-associated stroma is enriched in Cav1 ► Stromal Cav1 promotes local tumor invasion and metastasis
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2011.05.040