Cancer-associated Fibroblasts Promote Directional Cancer Cell Migration by Aligning Fibronectin

J Cell Biol. 2017 Nov 6;216(11):3799-3816. doi: 10.1083/jcb.201704053. Epub 2017 Oct 11.

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 (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.

Publication types

  • Video-Audio Media

MeSH terms

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

Substances

  • FN1 protein, human
  • Fibronectins
  • Integrin alpha5beta1
  • Receptor, Platelet-Derived Growth Factor alpha
  • Nonmuscle Myosin Type IIA