Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Nov 26

PMID 19931152

Citations 2016

Authors

Kandice R Levental

Hongmei Yu

Laura Kass

Johnathon N Lakins

Mikala Egeblad

Janine T Erler

Sheri F T Fong

Katalin Csiszar

Amato Giaccia

Wolfgang Weninger

Mitsuo Yamauchi

David L Gasser

Valerie M Weaver

Affiliations

Soon will be listed here.

Abstract

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.

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