Cytokine and Chemokine-Associated Signatures Underlying Dermal Invasion and Skin Metastasis in Melanoma

Metastatic spread remains the primary cause of mortality in melanoma. Our aim was to investigate the role of dermal endothelial cells in modulating melanoma cell invasiveness and cytokine/chemokine pattern. Primary melanoma cell lines were co-cultured with human dermal endothelial cells and assessed using Matrigel invasion assays. Invasive and non-invasive subpopulations were separated for gene expression analyses, and candidate molecules were further evaluated in patient tissue and plasma samples. Co-culture of melanoma and dermal endothelial cells revealed altered expression of several cytokine receptor genes (<i>CCR5</i>, <i>CXCR7</i>, <i>IL1RAPL2</i>, <i>IL4R</i>, <i>IL6ST</i>, <i>IL18R1</i>, <i>IL22RA2</i>, <i>TNFRSF10A</i>, <i>TNFRSF11B</i>, and <i>TNFRSF21</i>). Analysis of clinical melanoma samples showed significant downregulation of <i>IL1RAPL2</i> and <i>TNFRSF10A</i> in cutaneous metastases, whereas <i>IL6ST</i> expression correlated with Breslow thickness of the primary tumor rather than metastatic site. Proteome profiling of dermal endothelial cells revealed alterations in Midkine, GROα, MIP-3α, IL-8, and SDF-1 following co-culture with melanoma cells. Plasma measurements in melanoma patients confirmed elevated Midkine levels in skin metastases and decreased MIP-3α in metastatic disease. These results highlight potential cytokine and chemokine-mediated pathways involved in melanoma dermal invasion and cutaneous metastasis. While some findings did not reach statistical significance, concordant trends between in vitro and patient-derived data suggest their relevance and warrant further investigation in larger cohorts.