Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.

<h4>Background</h4>The diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment. We have previously demonstrated that the morphological and functional...

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Autores principales:	Mariusz L Hartman, Beata Talar, Muhammad Zaeem Noman, Anna Gajos-Michniewicz, Salem Chouaib, Malgorzata Czyz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5b1ff2f6f7964134a9bd8aa369a7e971
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spelling	oai:doaj.org-article:5b1ff2f6f7964134a9bd8aa369a7e9712021-11-18T08:23:26ZGene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.1932-620310.1371/journal.pone.0095157https://doaj.org/article/5b1ff2f6f7964134a9bd8aa369a7e9712014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24733089/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment. We have previously demonstrated that the morphological and functional phenotypes of melanoma can be dynamically altered upon external stimuli.<h4>Findings</h4>In the present study, transcriptome profiles were generated to explore the molecules governing phenotypes of melanospheres grown in the bFGF(+)EGF(+) serum-free cultures and monolayers maintained in the serum-containing medium. Higher expression levels of MITF-dependent genes that are responsible for differentiation, e.g., TYR and MLANA, and stemness-related genes, e.g., ALDH1A1, were detected in melanospheres. These results were supported by the observation that the melanospheres contained more pigmented cells and cells exerting the self-renewal capacity than the monolayers. In addition, the expression of the anti-apoptotic, MITF-dependent genes e.g., BCL2A1 was also higher in the melanospheres. The enhanced activity of MITF in melanospheres, as illustrated by the increased expression of 74 MITF-dependent genes, identified MITF as a central transcriptional regulator in melanospheres. Importantly, several genes including MITF-dependent ones were expressed in melanospheres and original tumors at similar levels. The reduced MITF level in monolayers might be partially explained by suppression of the Wnt/β-catenin pathway, and DKK1, a secreted inhibitor of this pathway, was highly up-regulated in monolayers in comparison to melanospheres and original tumors. Furthermore, the silencing of DKK1 in monolayers increased the percentage of cells with self-renewing capacity.<h4>Conclusions</h4>Our study indicates that melanospheres can be used to unravel the molecular pathways that sustain intratumoral phenotypic heterogeneity. Melanospheres directly derived from tumor specimens more accurately mirrored the morphology and gene expression profiles of the original tumors compared to monolayers. Therefore, melanospheres represent a relevant preclinical tool to study new anticancer treatment strategies.Mariusz L HartmanBeata TalarMuhammad Zaeem NomanAnna Gajos-MichniewiczSalem ChouaibMalgorzata CzyzPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e95157 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mariusz L Hartman Beata Talar Muhammad Zaeem Noman Anna Gajos-Michniewicz Salem Chouaib Malgorzata Czyz Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.
description	<h4>Background</h4>The diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment. We have previously demonstrated that the morphological and functional phenotypes of melanoma can be dynamically altered upon external stimuli.<h4>Findings</h4>In the present study, transcriptome profiles were generated to explore the molecules governing phenotypes of melanospheres grown in the bFGF(+)EGF(+) serum-free cultures and monolayers maintained in the serum-containing medium. Higher expression levels of MITF-dependent genes that are responsible for differentiation, e.g., TYR and MLANA, and stemness-related genes, e.g., ALDH1A1, were detected in melanospheres. These results were supported by the observation that the melanospheres contained more pigmented cells and cells exerting the self-renewal capacity than the monolayers. In addition, the expression of the anti-apoptotic, MITF-dependent genes e.g., BCL2A1 was also higher in the melanospheres. The enhanced activity of MITF in melanospheres, as illustrated by the increased expression of 74 MITF-dependent genes, identified MITF as a central transcriptional regulator in melanospheres. Importantly, several genes including MITF-dependent ones were expressed in melanospheres and original tumors at similar levels. The reduced MITF level in monolayers might be partially explained by suppression of the Wnt/β-catenin pathway, and DKK1, a secreted inhibitor of this pathway, was highly up-regulated in monolayers in comparison to melanospheres and original tumors. Furthermore, the silencing of DKK1 in monolayers increased the percentage of cells with self-renewing capacity.<h4>Conclusions</h4>Our study indicates that melanospheres can be used to unravel the molecular pathways that sustain intratumoral phenotypic heterogeneity. Melanospheres directly derived from tumor specimens more accurately mirrored the morphology and gene expression profiles of the original tumors compared to monolayers. Therefore, melanospheres represent a relevant preclinical tool to study new anticancer treatment strategies.
format	article
author	Mariusz L Hartman Beata Talar Muhammad Zaeem Noman Anna Gajos-Michniewicz Salem Chouaib Malgorzata Czyz
author_facet	Mariusz L Hartman Beata Talar Muhammad Zaeem Noman Anna Gajos-Michniewicz Salem Chouaib Malgorzata Czyz
author_sort	Mariusz L Hartman
title	Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.
title_short	Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.
title_full	Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.
title_fullStr	Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.
title_full_unstemmed	Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.
title_sort	gene expression profiling identifies microphthalmia-associated transcription factor (mitf) and dickkopf-1 (dkk1) as regulators of microenvironment-driven alterations in melanoma phenotype.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/5b1ff2f6f7964134a9bd8aa369a7e971
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Gene expression profiling identifies microphthalmia-associated transcription factor (MITF) and Dickkopf-1 (DKK1) as regulators of microenvironment-driven alterations in melanoma phenotype.

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