Matrix metalloproteinases (MMP) are crucial in remodeling the extracellular matrix during physiological and pathological processes with diverse and complex activities. Imbalances in proteolysis contribute to the pathogenesis of many skin diseases, including fibrosis and cancer. In melanoma, a strong expression of MMP14 is detected in tumor cells and peritumoral cells. Although the functional significance for this protease in melanoma cells is better understood, it is unclear which role it has in peritumoral stromal cells. In skin, in vivo deletion of MMP14 in fibroblasts leads to a fibrotic-like phenotype with increased dermal thickness, collagen type I content, and tissue stiffness because of loss of collagen lysis, but not synthesis. Surprisingly, melanoma growth in the fibrotic-like dermis of these mice was decreased, accompanied by reduced cellular proliferation and vascularization. Tissue stiffness in peritumoral areas lacking fibroblasts-derived MMP14, detected by atomic force microscopy, was increased in early but not late melanoma. However, peritumoral tissue in late melanoma contained more collagen but not altered cross-linkage than controls. Culture of melanoma cells on high stiffness surfaces in combination with high amounts of fibrillar collagen type I showed reduced proliferation. Comparably, the growth of melanoma spheroids in 3D systems having high fibrillar collagen type I concentrations was inhibited. In addition, the growth of melanoma in bleomycin-induced fibrotic skin lesions of control mice was reduced. In summary, we show that the expression of stromal fibroblast-MMP14 controls melanoma growth by modifying the peritumoral extracellular matrix and suggest that increased collagen accumulation is an obstacle to melanoma growth.

ESDR274 - Role of fibroblast-MMP14 in melanoma growth

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING