Matrix crosslinking forces tumor progression by enhancing integrin signaling.
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.
Levental
Kandice R
KR
Department of Bioengineering and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yu
Hongmei
H
Kass
Laura
L
Lakins
Johnathon N
JN
Egeblad
Mikala
M
Erler
Janine T
JT
Fong
Sheri F T
SF
Csiszar
Katalin
K
Giaccia
Amato
A
Weninger
Wolfgang
W
Yamauchi
Mitsuo
M
Gasser
David L
DL
Weaver
Valerie M
VM
D000375:Aging; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D015398:Signal Transduction
D016023:Integrins; D004815:Epidermal Growth Factor; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase