Abstract
Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast’s matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast’s deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14.
Highlights
This article is an open access articleMatrix metalloproteinases (MMPs) are calcium-dependent, zinc-containing endopeptidases crucial for tissue remodeling during development and adulthood
Tumor growth depends on events such as cell proliferation, migration, and invasion regulated by tumor cell-autonomous and cell-extrinsic mechanisms modulated by the interaction with the surrounding tumor microenvironment
Several in vitro studies, including ours [14], indicate a negative role of high tissue stiffness and fibrillar collagen concentration on melanoma cell growth and migration [37,38,39,40]. In line with these findings, we found reduced melanoma growth in vivo when collagens were increased in the dermis due to
Summary
Matrix metalloproteinases (MMPs) are calcium-dependent, zinc-containing endopeptidases crucial for tissue remodeling during development and adulthood They can degrade extracellular matrix (ECM) proteins and play an essential role in tissue turnover to maintain tissue homeostasis. Their dysregulation is associated with several pathological conditions such as fibrosis and cancer [1]. Collagens are a large superfamily of 28 different types presenting the most abundant proteins in the extracellular matrix of vertebrates They are functional in maintaining tissue structure, stability, and mechanical properties [15,16] and are regulators of several cellular functions, including proliferation, apoptosis, differentiation, adhesion, and migration [17,18,19,20,21,22]. Types V, VI, XII, XIV, and XVI are present in lower amounts [23]
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