Matrix crosslinking forces tumor progression by enhancing integrin signaling.

TitleMatrix crosslinking forces tumor progression by enhancing integrin signaling.
Publication TypeJournal Article
Year of Publication2009
AuthorsLevental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SFT, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM
JournalCell
Volume139
Issue5
Pagination891-906
Date Published2009 Nov 25
ISSN1097-4172
KeywordsAging, Animals, Breast Neoplasms, Collagen, Epidermal Growth Factor, Extracellular Matrix, Female, Fibrosis, Genes, ras, Humans, Integrins, Mammary Glands, Human, Mice, Mice, Inbred BALB C, Protein-Lysine 6-Oxidase, Signal Transduction
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.

DOI10.1016/j.cell.2009.10.027
Alternate JournalCell
PubMed ID19931152
PubMed Central IDPMC2788004
Grant ListR01 CA078731-04 / CA / NCI NIH HHS / United States
R01 CA078731-05 / CA / NCI NIH HHS / United States
R01 CA078731-06 / CA / NCI NIH HHS / United States
R01 CA078731-07 / CA / NCI NIH HHS / United States
R01 CA078731-08 / CA / NCI NIH HHS / United States
R01 CA138818 / CA / NCI NIH HHS / United States
R01 CA138818-03 / CA / NCI NIH HHS / United States
R01-CA057621 / CA / NCI NIH HHS / United States
R01-CA078731 / CA / NCI NIH HHS / United States
T32HL00795404 / HL / NHLBI NIH HHS / United States
U54CA143836 / CA / NCI NIH HHS / United States
Weaver