Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Area of Science:

• Dermatology
• Oncology
• Biochemistry

Background:

• Skin homeostasis relies on extracellular matrix (ECM) balance.
• Matrix metalloproteinase-14 (MMP14) in dermal fibroblasts is crucial for ECM degradation.
• MMP14 deficiency in fibroblasts causes skin fibrosis and collagen accumulation.

Purpose of the Study:

• To investigate the role of fibroblast-derived MMP14 in melanoma progression.
• To determine how altered ECM in fibrotic skin affects tumor growth and characteristics.

Main Methods:

• Mice lacking MMP14 in dermal fibroblasts (MMP14Sf-/-) were used.
• Melanoma growth, proliferation, and vascularization were assessed.
• Atomic force microscopy measured matrix stiffness.
• Ex vivo and in vitro assays evaluated melanoma cell invasion and growth.

Main Results:

• Melanoma growth, proliferation, and vessel density were reduced in MMP14Sf-/- mice.
• Peritumoral matrix stiffness increased in early melanomas lacking fibroblast MMP14.
• Melanoma cells formed smaller islands in MMP14Sf-/- skin, indicating restricted invasion.
• In vitro, melanoma growth was inhibited on stiff substrates and in high-collagen 3D cultures.
• Bleomycin-induced fibrosis in vivo reduced melanoma tumor growth.

Conclusions:

• Fibroblast MMP14 regulates melanoma progression by modifying the tumor microenvironment.
• Increased collagen accumulation and matrix stiffness in fibrotic skin act as negative regulators of melanoma.
• Targeting MMP14 or promoting fibrosis could be potential therapeutic strategies for melanoma.