Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.

Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
J Cell Biol. 2017 216 (11): 3799-3816

PMID: 29021221 · PMCID: PMC5674895 · DOI:10.1083/jcb.201704053

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 (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We 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.

© 2017 Erdogan et al.

MeSH Terms (20)

Cancer-Associated Fibroblasts Cell Communication Cell Line, Tumor Cell Movement Coculture Techniques Extracellular Matrix Fibronectins Humans Integrin alpha5beta1 Male Mechanotransduction, Cellular Neoplasm Invasiveness Nonmuscle Myosin Type IIA Prostatic Neoplasms Receptor, Platelet-Derived Growth Factor alpha RNA Interference Time Factors Transfection Tumor Cells, Cultured Tumor Microenvironment

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