We conclude that (i) altered expression of stem cell pluripotency and Ca2+ signaling pathway-related genes may contribute to metastatic transformation, and (ii) CTNNB1, GNAQ, GSK3B, GSTP1, MAPK3, PPP1CC, PRKACA, SMAD4, and especially PTPN11 may represent an optimal candidate group of biomarkers and in silico therapeutic targets for melanoma metastasis. Here, SMAD4 is linked to melanoma.