Microenvironment and Immunology Snail1-Expressing Fibroblasts in the Tumor Microenvironment Display Mechanical Properties That Support Metastasis

Crosstalk between tumor and stromal cells in the tumormicro-environment alter its properties in ways that facilitate the invasive behavior of tumor cells. Here, we demonstrate that cancer-asso-ciated fibroblasts (CAF) increase the stiffness of the extracellular matrix (ECM) and promote anisotropic fiber orientation, two mechanical signals generated through a Snail1/RhoA/aSMA– dependent mechanism that sustains oriented tumor cell migra-tion and invasiveness. Snail1-depleted CAF failed to acquire myofibroblastic traits in response to TGFb, including RhoA acti-vation, aSMA-positive stress fibers, increased fibronectin fibrillo-genesis, and production of a stiff ECMwith oriented fibers. Snail1 expression in human tumor–derived CAF was associated with an ability to organize the ECM. In coculture, a relatively smaller number of Snail1-expressing CAF were capable of imposing an anisotropic ECM architecture, compared with nonactivated fibro-blasts. Pathologically, human breast cancers with Snail1þ CAF tended to exhibit desmoplastic areas with anisotropic fibers, lymph node involvement, and poorer outcomes. Snail1 involve-ment in driving an ordered ECMwas further confirmed inwound-healing experiments inmice,with Snail1 depletion preventing the anisotropic organization of granulation tissue and delaying wound healing. Overall, our results showed that inhibiting Snail1 function in CAF could prevent tumor-driven ECM reorganization and cancer invasion. Cancer Res; 1–12. 2014 AACR