NK cell editing mediates Epithelial to Mesenchymal Transition via phenotypic and proteomic changes in melanoma cell lines

Tumor cell plasticity is a major obstacle for the cure of malignancies as it makes tumor cells highly adaptable to micro-environmental changes, enables their phenotype switching among different forms, and favors the generation of pro-metastatic tumor cell subsets. Phenotype switching towards more aggressive forms involves different functional, phenotypic and morphologic changes, which are often related to the process known as Epithelial-Mesenchymal Transition (EMT). In this study, we report NK cells may increase the malignancy of melanoma cells by inducing changes relevant to EMT and, more broadly, to phenotype switching from proliferative to invasive forms. In co-culture, NK cells induced effects on tumor cells similar to those induced by EMT-promoting cytokines, including up-regulation of stemness and EMT markers, morphologic transition, inhibition of proliferation, and increased capacity for matrigel invasion. Most changes were dependent on the engagement of NKp30 or NKG2D and the release of cytokines including IFN-γ and TNF-α. Moreover, EMT induction also favored escape from NK cell attack. Melanoma cells undergoing EMT either increased NK-protective HLA-I expression on their surface or downregulated several tumor-recognizing activating receptors on NK cells. Mass spectrometry-based proteomic analysis revealed in two different melanoma cell lines a partial overlap between proteomic profiles induced by NK cells or by EMT-cytokines, indicating that various processes or pathways related to tumor progression are induced by exposure to NK cells.

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