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Updated: Nov 7, 2025
Rapid Generation of Primary Murine Melanocyte and Fibroblast Cultures
Published on: June 26, 2019
Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth
Elke Pach1, Jürgen Brinckmann2, Matthias Rübsam3
1Department of Dermatology and Venereology, Faculty of Medicine, University of Cologne, Hospital Cologne, 50937 Cologne, Germany.
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.
Insights
Fibrosis, or skin scarring, can inhibit melanoma growth by altering the tumor microenvironment. Matrix metalloproteinase-14 (MMP14) in fibroblasts promotes collagen accumulation, which suppresses melanoma progression.
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.
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