Integrin Signaling Laboratory

Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC)

We have shown that crucial cell functions are affected by key mechanoregulatory molecules: integrins (which mediate cell adhesion to the extracellular matrix), Rac/Rho GTPases (which regulate actin cytoskeleton functions & mechanical contractility), and caveolae-resident proteins. Caveolae are actinlinked plasma membrane invaginations abundant in mechanically stressed tissues (including heart, vessels, muscle & fat) and are involved in signaling, viral entry, membrane trafficking & lipid metabolism.

The precise functions of caveolae and their main constituent proteins caveolins (Cav 1-3) and cavins (1-4) remain unresolved. Cav-deficient mice show tissue abnormalities, and caveolar disorders are associated with lipodystrophy, muscular dystrophy, osteoporosis, CVD and cancer. We and others have shown that caveolae can sense and transduce mechanical cues. We found that Cav1 can modulate cell shape and responses via force-dependent remodeling of the 3D microenvironment. Elongated cancer associated fibroblasts (CAFs) form stiff, parallel-fiber networks through which cancer cells move rapidly, invading and metastasizing. Our work shows that stromal-Cav1 drives not only pathological remodeling of the tumor microenvironment, but also physiological remodeling, for example in the mammary gland and the skin. We are now addressing the role of Cav1 in cardiac remodeling after acute myocardial infarction using the LAD (left anterior descending) artery permanent ligation model. Abnormal cardiac remodeling and fibrosis after acute myocardial infarction can lead to heart failure and death. Rac1 had been detected in the nucleus, and our work has provided insight into the molecular mechanism of Rac1 nucleocytoplasmic shuttling. Rac1-driven nuclear actin polymerization controls nuclear membrane organization and shape. Dysregulation of this mechanism in cancer leads to Rac1 nuclear accumulation, promoting nuclear deformation and cell invasion through narrow spaces.

In 2015 we also established Cav1 as a major checkpoint in the transition from an epithelial to a mesenchymal identity in the peritoneum, through the suppression of MEK-ERK1/2-Snail1 signaling. The efficacy of a MEK pharmacological inhibitor in counteracting the EMT/fibrosis developed in Cav1-/- mice during peritoneal dialysis warrants further translational studies in other chronic inflammatory diseases.

Molecular Biomedicine