Increased traction forces by cancer-associated fibroblasts align fibronectin to direct cancer cell migration

Abstract

Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared to normal fibroblasts (NFs), CAFs produce a fibronectin (Fn)-rich extracellular matrix (ECM) with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing MyoII- and PDGFRa-mediated contractility and traction forces which are transduced to Fn through a5b1 integrin. We further show that prostate cancer cells use av integrin to migrate efficiently and directionally on CAF-derived matrices. We also demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.