Role of Organ-Specific Endothelial Cells in Melanoma Adhesion Patterns

Background: The metastatic dissemination of melanoma involves adhesion of circulating tumor cells within organ-specific vascular beds; however, the relative contribution of the endothelial environment versus that of the melanoma-intrinsic molecular state remains unclear. Materials and Methods: We quantified the in vitro adhesion of primary (n = 5) and metastatic (n = 3) melanoma cell lines to human hepatic, brain, and pulmonary endothelial cells under co-culture conditions, and we profiled the expression of 86 adhesion- and extracellular-matrix-related genes in melanoma and endothelial cells. Results: Adhesion was highest for the hepatic endothelium, intermediate for the pulmonary endothelium, and lowest for the brain endothelium. This endothelial preference was conserved in both primary and metastatic melanoma cells, though metastatic cells exhibited higher absolute adhesion. The linear mixed-effect models revealed that the effects of adhesion state on melanoma gene expression were modest and varied by endothelial type, whereas melanoma origin had more widespread and larger effects (mean absolute standardized coefficients of 0.32–0.47 versus 0.60–0.87, respectively). The expression of three genes (SPP1, ITGA11, and MMP2) was associated with melanoma origin in all endothelial types. Spearman’s co-expression analysis revealed endothelial-type-specific gene networks, and within-sample permutation confirmed the non-random coordination in all three endothelial types. Conclusions: Our findings support a model in which endothelial organ specificity contributes to melanoma cell adhesion behavior and associated transcriptional patterns, highlighting the importance of the vascular interface as a biologically active mediator of early metastatic cell–endothelium interactions.