The impact of cellular elements of TME on melanoma biology and its sensitivity to EGFR and MET targeted therapy.

Microenvironment of the melanoma consists of cellular elements like fibroblasts, adipocytes, and keratinocytes as well as extracellular matrix and physicochemical conditions. In our previous research, we have established that melanoma influences strongly above mentioned cells present in the tumor niche and recruits them to support cancer progression. In this work, we evaluated the impact of cancer-associated cells, namely fibroblasts (CAFs), adipocytes (CAAs), and keratinocytes (CAKs) on melanoma proliferation, signaling pathways activation, metabolism as well as the effectiveness of used anti-cancer therapy. Obtained results indicated elevated phosphorylation of STAT3, upregulated GLUT1 and GLUT3 as well as downregulated of MCT-1 expression level in melanoma cells under the influence of all examined cells present in the tumor niche. The proliferation of melanoma cells was increased after co-culture with CAFs and CAKs, while epithelial-mesenchymal transition markers' expression level was raised in the presence of CAFs and CAAs. The level of perilipin 2 and lipid content was elevated in melanoma cells under the influence of CAAs. Moreover, increased expression of CYP1A1, gene encoding drug metabolizing protein, in melanoma cells co-cultured with CAFs and CAKs prompted us to verify the effectiveness of the previously proposed by us anti-melanoma therapy based on combination of EGFR and MET inhibitors. Obtained results indicate that the designed therapy is still efficient, even if the fibroblasts, adipocytes, and keratinocytes, are present in the melanoma vicinity.