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Cancer Res. 2018 Jul 15;78(14):3913-3925. doi: 10.1158/0008-5472.CAN-17-1891. Epub 2018 May 11.

NK-cell Editing Mediates Epithelial-to-Mesenchymal Transition via Phenotypic and Proteomic Changes in Melanoma Cell Lines.

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UOC Immunologia, Ospedale Policlinico San Martino Genova, Genoa, Italy.
Department of Experimental Medicine (DIMES), University of Genova, Genoa, Italy.
Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
Istituto Giannina Gaslini, Genoa, Italy.
Core Facilities - Proteomics Laboratory, Istituto Giannina Gaslini, Genoa, Italy.
Group of Inverse Problems, Optimization and Machine Learning, Departamento de Matemáticas, Universidad de Oviedo, Oviedo, Spain.
Department of Functional Biology, IUOPA, University of Oviedo, Facultad de Medicina, Oviedo, Spain.
Department of Pathology, University of Brescia, Brescia, Italy.
Department of Pathology, Sacro Cuore Don Calabria Hospital, Negrar (VR), Italy.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Immunology Area, Ospedale Pediatrico Bambin Gesù, Rome, Italy.
UOC Immunologia, Ospedale Policlinico San Martino Genova, Genoa, Italy.
Contributed equally


Tumor cell plasticity is a major obstacle for the cure of malignancies as it makes tumor cells highly adaptable to microenvironmental changes, enables their phenotype switching among different forms, and favors the generation of prometastatic tumor cell subsets. Phenotype switching toward 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 natural killer (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 coculture, NK cells induced effects on tumor cells similar to those induced by EMT-promoting cytokines, including upregulation 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 IFNγ and TNFα. 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.Significance: NK cells can induce prometastatic properties on melanoma cells that escape from killing, providing important clues to improve the efficacy of NK cells in innovative antitumor therapies. Cancer Res; 78(14); 3913-25. ©2018 AACR.

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