Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer

Integrin alpha 11 beta 1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin alpha 11 (alpha 11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these alpha 11 knockout (alpha 11(-/-)) mice was significantly impeded, as compared with wild-type (alpha 11(+/+)) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of alpha 11(-/-) and alpha 11(+/+) mice showed significant reduction in the metastatic potential of these cells in the alpha 11(-/-) mice. We identified that collagen cross-linking is associated with stromal alpha 11 expression, and the loss of tumor stromal alpha 11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin alpha 11 beta 1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for alpha 11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.