NK-cell editing mediates epithelial-to-mesenchymal transition via phenotypic and proteomic changes in melanoma cell lines

Leticía Huergo-Zapico, Monica Parodi, Claudia Cantoni, Chiara Lavarello, Juan L. Fernández-Martínez, Andrea Petretto, Enrique J. DeAndrés-Galiana, Mirna Balsamo, Alejandro López-Soto, Gabriella Pietra, Mattia Bugatti, Enrico Munari, Marcella Marconi, Maria Cristina Mingari, William Vermi, Lorenzo Moretta, Segundo González, Massimo Vitale

Research output: Contribution to journalArticle

Abstract

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 IFNg and TNFa. 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.

Original languageEnglish
Pages (from-to)3913-3925
Number of pages13
JournalCancer Research
Volume78
Issue number14
DOIs
Publication statusPublished - Jul 15 2018

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Epithelial-Mesenchymal Transition
Natural Killer Cells
Proteomics
Melanoma
Cell Line
Neoplasms
Cytokines
Phenotype
Natural Killer Cell Receptors
Investigational Therapies
Coculture Techniques
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

NK-cell editing mediates epithelial-to-mesenchymal transition via phenotypic and proteomic changes in melanoma cell lines. / Huergo-Zapico, Leticía; Parodi, Monica; Cantoni, Claudia; Lavarello, Chiara; Fernández-Martínez, Juan L.; Petretto, Andrea; DeAndrés-Galiana, Enrique J.; Balsamo, Mirna; López-Soto, Alejandro; Pietra, Gabriella; Bugatti, Mattia; Munari, Enrico; Marconi, Marcella; Mingari, Maria Cristina; Vermi, William; Moretta, Lorenzo; González, Segundo; Vitale, Massimo.

In: Cancer Research, Vol. 78, No. 14, 15.07.2018, p. 3913-3925.

Research output: Contribution to journalArticle

Huergo-Zapico, L, Parodi, M, Cantoni, C, Lavarello, C, Fernández-Martínez, JL, Petretto, A, DeAndrés-Galiana, EJ, Balsamo, M, López-Soto, A, Pietra, G, Bugatti, M, Munari, E, Marconi, M, Mingari, MC, Vermi, W, Moretta, L, González, S & Vitale, M 2018, 'NK-cell editing mediates epithelial-to-mesenchymal transition via phenotypic and proteomic changes in melanoma cell lines', Cancer Research, vol. 78, no. 14, pp. 3913-3925. https://doi.org/10.1158/0008-5472.CAN-17-1891
Huergo-Zapico, Leticía ; Parodi, Monica ; Cantoni, Claudia ; Lavarello, Chiara ; Fernández-Martínez, Juan L. ; Petretto, Andrea ; DeAndrés-Galiana, Enrique J. ; Balsamo, Mirna ; López-Soto, Alejandro ; Pietra, Gabriella ; Bugatti, Mattia ; Munari, Enrico ; Marconi, Marcella ; Mingari, Maria Cristina ; Vermi, William ; Moretta, Lorenzo ; González, Segundo ; Vitale, Massimo. / NK-cell editing mediates epithelial-to-mesenchymal transition via phenotypic and proteomic changes in melanoma cell lines. In: Cancer Research. 2018 ; Vol. 78, No. 14. pp. 3913-3925.
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AU - Huergo-Zapico, Leticía

AU - Parodi, Monica

AU - Cantoni, Claudia

AU - Lavarello, Chiara

AU - Fernández-Martínez, Juan L.

AU - Petretto, Andrea

AU - DeAndrés-Galiana, Enrique J.

AU - Balsamo, Mirna

AU - López-Soto, Alejandro

AU - Pietra, Gabriella

AU - Bugatti, Mattia

AU - Munari, Enrico

AU - Marconi, Marcella

AU - Mingari, Maria Cristina

AU - Vermi, William

AU - Moretta, Lorenzo

AU - González, Segundo

AU - Vitale, Massimo

PY - 2018/7/15

Y1 - 2018/7/15

N2 - 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 IFNg and TNFa. 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.

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