Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value

The use of patient-derived primary cell cultures in cancer preclinical assays, including drug screens and genotoxic studies, has increased in recent years. However, their translational value is constrained by several limitations, including variability that can be caused by the culture conditions. He...

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Autores principales:	Ahmad Najem, Jasper Wouters, Mohammad Krayem, Florian Rambow, Malak Sabbah, François Sales, Ahmad Awada, Stein Aerts, Fabrice Journe, Jean-Christophe Marine, Ghanem E. Ghanem
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	melanoma primary cultures phenotype switching tyrosine pigmentation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/7246698bc874445fae20d2e08f486791
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spelling	oai:doaj.org-article:7246698bc874445fae20d2e08f4867912021-11-11T04:43:56ZTyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value2234-943X10.3389/fonc.2021.780654https://doaj.org/article/7246698bc874445fae20d2e08f4867912021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.780654/fullhttps://doaj.org/toc/2234-943XThe use of patient-derived primary cell cultures in cancer preclinical assays, including drug screens and genotoxic studies, has increased in recent years. However, their translational value is constrained by several limitations, including variability that can be caused by the culture conditions. Here, we show that the medium composition commonly used to propagate primary melanoma cultures has limited their representability of their tumor of origin and their cellular plasticity, and modified their sensitivity to therapy. Indeed, we established and compared cultures from different melanoma patients propagated in parallel in low-tyrosine (Ham’s F10) or in high-tyrosine (Ham’s F10 supplemented with tyrosine or RPMI1640 or DMEM) media. Tyrosine is the precursor of melanin biosynthesis, a process particularly active in differentiated melanocytes and melanoma cells. Unexpectedly, we found that the high tyrosine concentrations promoted an early phenotypic drift towards either a mesenchymal-like or senescence-like phenotype, and prevented the establishment of cultures of melanoma cells harboring differentiated features, which we show are frequently present in human clinical biopsies. Moreover, the invasive phenotype emerging in these culture conditions appeared irreversible and, as expected, associated with intrinsic resistance to MAPKi. In sharp contrast, differentiated melanoma cell cultures retained their phenotypes upon propagation in low-tyrosine medium, and importantly their phenotypic plasticity, a key hallmark of melanoma cells. Altogether, our findings underline the importance of culturing melanoma cells in low-tyrosine-containing medium in order to preserve their phenotypic identity of origin and cellular plasticity.Ahmad NajemJasper WoutersJasper WoutersMohammad KrayemFlorian RambowFlorian RambowMalak SabbahFrançois SalesFrançois SalesAhmad AwadaAhmad AwadaStein AertsStein AertsFabrice JourneFabrice JourneJean-Christophe MarineJean-Christophe MarineGhanem E. GhanemFrontiers Media S.A.articlemelanomaprimary culturesphenotype switchingtyrosinepigmentationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	melanoma primary cultures phenotype switching tyrosine pigmentation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	melanoma primary cultures phenotype switching tyrosine pigmentation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ahmad Najem Jasper Wouters Jasper Wouters Mohammad Krayem Florian Rambow Florian Rambow Malak Sabbah François Sales François Sales Ahmad Awada Ahmad Awada Stein Aerts Stein Aerts Fabrice Journe Fabrice Journe Jean-Christophe Marine Jean-Christophe Marine Ghanem E. Ghanem Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value
description	The use of patient-derived primary cell cultures in cancer preclinical assays, including drug screens and genotoxic studies, has increased in recent years. However, their translational value is constrained by several limitations, including variability that can be caused by the culture conditions. Here, we show that the medium composition commonly used to propagate primary melanoma cultures has limited their representability of their tumor of origin and their cellular plasticity, and modified their sensitivity to therapy. Indeed, we established and compared cultures from different melanoma patients propagated in parallel in low-tyrosine (Ham’s F10) or in high-tyrosine (Ham’s F10 supplemented with tyrosine or RPMI1640 or DMEM) media. Tyrosine is the precursor of melanin biosynthesis, a process particularly active in differentiated melanocytes and melanoma cells. Unexpectedly, we found that the high tyrosine concentrations promoted an early phenotypic drift towards either a mesenchymal-like or senescence-like phenotype, and prevented the establishment of cultures of melanoma cells harboring differentiated features, which we show are frequently present in human clinical biopsies. Moreover, the invasive phenotype emerging in these culture conditions appeared irreversible and, as expected, associated with intrinsic resistance to MAPKi. In sharp contrast, differentiated melanoma cell cultures retained their phenotypes upon propagation in low-tyrosine medium, and importantly their phenotypic plasticity, a key hallmark of melanoma cells. Altogether, our findings underline the importance of culturing melanoma cells in low-tyrosine-containing medium in order to preserve their phenotypic identity of origin and cellular plasticity.
format	article
author	Ahmad Najem Jasper Wouters Jasper Wouters Mohammad Krayem Florian Rambow Florian Rambow Malak Sabbah François Sales François Sales Ahmad Awada Ahmad Awada Stein Aerts Stein Aerts Fabrice Journe Fabrice Journe Jean-Christophe Marine Jean-Christophe Marine Ghanem E. Ghanem
author_facet	Ahmad Najem Jasper Wouters Jasper Wouters Mohammad Krayem Florian Rambow Florian Rambow Malak Sabbah François Sales François Sales Ahmad Awada Ahmad Awada Stein Aerts Stein Aerts Fabrice Journe Fabrice Journe Jean-Christophe Marine Jean-Christophe Marine Ghanem E. Ghanem
author_sort	Ahmad Najem
title	Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value
title_short	Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value
title_full	Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value
title_fullStr	Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value
title_full_unstemmed	Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value
title_sort	tyrosine-dependent phenotype switching occurs early in many primary melanoma cultures limiting their translational value
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7246698bc874445fae20d2e08f486791
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Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value

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