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.