Abstract
Lymphatic invasion and accumulation of continuous collagen bundles around tumor cells are associated with poor melanoma prognosis, but the underlying mechanisms and molecular determinants have remained unclear. We show here that a copy-number gain or overexpression of the membrane-type matrix metalloproteinase MMP16 (MT3-MMP) is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. In cultured WM852 melanoma cells derived from human melanoma metastasis, silencing of MMP16 resulted in cell-surface accumulation of the MMP16 substrate MMP14 (MT1-MMP) as well as L1CAM cell adhesion molecule, identified here as a novel MMP16 substrate. When limiting the activities of these trans-membrane protein substrates toward pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP16 supported nodular-type growth of adhesive collagen-surrounded melanoma cell nests, coincidentally steering cell collectives into lymphatic vessels. These results uncover a novel mechanism in melanoma pathogenesis, whereby restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, revealing MMP16 as a putative indicator of adverse melanoma prognosis.
Highlights
Melanoma is the most aggressive skin cancer in humans, occurring at a younger age than other common malignancies [1]
Melanomas with MMP16 overexpression segregated into poor outcome groups (Fig. 1B; primary and Fig. 1C; metastasis), whereas high MMP14 expression across the biopsies did not vary according to survival (Supplementary Fig. S1B and S1C)
We show that the overexpression of as yet poorly characterized MMP16 is associated with both the growth pattern of tumor cell nests toward outlining continuous collagen and lymphatic vessel invasion (LVI) in primary human melanomas
Summary
Melanoma is the most aggressive skin cancer in humans, occurring at a younger age than other common malignancies [1]. The prognosis of metastatic melanoma remains unfavorable due to melanoma plasticity and lack of effective treatments. The most accurate predictors of melanoma progression are tumor thickness, ulceration, mitotic index, and sentinel lymph node (SLN) metastasis [2]. Patients with >1-mm-thick tumors are directed for SLN biopsy [2]. SLN biopsy procedure is associated with increased morbidity, and the impact on survival is questionable [3]. A better understanding of the mechanisms and early markers of melanoma progression is essential. Lymphatic vessel density, lymphatic invasion, and extracellular matrix (ECM) assembly in parallel bundles and networks have been implicated as additional parameters
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