These ideas stem from converging lines of evidence that melanoma cells up-regulate genes related to synaptic scaffold proteins, alter perivascular matrix components, and exhibit an extensive heterogeneity of both voltage-gated and mechanically sensitive ion channels; endothelial and neuronal elements reciprocally display changes in gene expression; and spatially resolved datasets are increasingly showing adjacency patterns which suggest cross-talk between neurons and melanoma cells rather than just simple co-optation [66]. This evidence concerns the gene PROS1 and melanoma.