Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Abstract

Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14Sf−/−) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired proteolysis. Here, we show that melanoma growth in these mouse fibrotic dermal samples was decreased, paralleled by reduced tumor cell proliferation and vessel density. Using atomic force microscopy, we found increased peritumoral matrix stiffness of early but not late melanomas in the absence of fibroblast-derived MMP14. However, total collagen levels were increased at late melanoma stages in MMP14Sf−/− mice compared to controls. In ex vivo invasion assays, melanoma cells formed smaller tumor islands in MMP14Sf−/− skin, indicating that MMP14-dependent matrix accumulation regulates tumor growth. In line with these data, in vitro melanoma cell growth was inhibited in high collagen 3D spheroids or stiff substrates. Most importantly, in vivo induction of fibrosis using bleomycin reduced melanoma tumor growth. In summary, we show that MMP14 expression in stromal fibroblasts regulates melanoma tumor progression by modifying the peritumoral matrix and point to collagen accumulation as a negative regulator of melanoma.