Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP

TLDR

Cancer cells traverse collagen‑rich extracellular matrix barriers by adopting a fibroblast‑like phenotype and engaging undefined proteolytic cascades that mediate invasion. Using fibroblasts from gene‑targeted mice, the authors identified an MMP‑dependent activity driving invasion independently of plasminogen, gelatinases, collagenases, or stromelysin‑1. Fibroblasts and cancer cells exhibit indistinguishable pericellular collagenolytic activity that enables ECM traversal, and deletion or suppression of MT1‑MMP abolishes this activity in vitro and in vivo, establishing MT1‑MMP as the major cell‑associated protease required for invasive behavior.

Abstract

As cancer cells traverse collagen-rich extracellular matrix (ECM) barriers and intravasate, they adopt a fibroblast-like phenotype and engage undefined proteolytic cascades that mediate invasive activity. Herein, we find that fibroblasts and cancer cells express an indistinguishable pericellular collagenolytic activity that allows them to traverse the ECM. Using fibroblasts isolated from gene-targeted mice, a matrix metalloproteinase (MMP)–dependent activity is identified that drives invasion independently of plasminogen, the gelatinase A/TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2, or stromelysin-1. In contrast, deleting or suppressing expression of the membrane-tethered MMP, MT1-MMP, in fibroblasts or tumor cells results in a loss of collagenolytic and invasive activity in vitro or in vivo. Thus, MT1-MMP serves as the major cell-associated proteinase necessary to confer normal or neoplastic cells with invasive activity.