Matrix crosslinking forces tumor progression by enhancing integrin signaling

TY - JOUR

T1 - Matrix crosslinking forces tumor progression by enhancing integrin signaling

AU - Levental, Kandice R

AU - Yu, Hongmei

AU - Kass, Laura

AU - Lakins, Johnathon N

AU - Egeblad, Mikala

AU - Erler, Janine Terra

AU - Fong, Sheri F T

AU - Csiszar, Katalin

AU - Giaccia, Amato

AU - Weninger, Wolfgang

AU - Yamauchi, Mitsuo

AU - Gasser, David L

AU - Weaver, Valerie M

PY - 2009/11/25

Y1 - 2009/11/25

N2 - 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.

AB - 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.

KW - Aging

KW - Animals

KW - Breast Neoplasms

KW - Collagen

KW - Epidermal Growth Factor

KW - Extracellular Matrix

KW - Female

KW - Fibrosis

KW - Genes, ras

KW - Humans

KW - Integrins

KW - Mammary Glands, Human

KW - Mice

KW - Mice, Inbred BALB C

KW - Protein-Lysine 6-Oxidase

KW - Signal Transduction

U2 - 10.1016/j.cell.2009.10.027

DO - 10.1016/j.cell.2009.10.027

M3 - Journal article

C2 - 19931152

SN - 0092-8674

VL - 139

SP - 891

EP - 906

JO - Cell

JF - Cell

IS - 5

ER -