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Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program
Melanoma plasticity creates a plethora of opportunities for cancer cells to escape treatment. Thus, therapies must target all cancer cell subpopulations bearing the potential to contribute to disease. The role of the differentiation/pigmentation program in intrinsic and acquired drug resistance is l...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636509/ https://www.ncbi.nlm.nih.gov/pubmed/31354817 http://dx.doi.org/10.1155/2019/1697913 |
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author | Czyz, Malgorzata Sztiller-Sikorska, Malgorzata Gajos-Michniewicz, Anna Osrodek, Marta Hartman, Mariusz L. |
author_facet | Czyz, Malgorzata Sztiller-Sikorska, Malgorzata Gajos-Michniewicz, Anna Osrodek, Marta Hartman, Mariusz L. |
author_sort | Czyz, Malgorzata |
collection | PubMed |
description | Melanoma plasticity creates a plethora of opportunities for cancer cells to escape treatment. Thus, therapies must target all cancer cell subpopulations bearing the potential to contribute to disease. The role of the differentiation/pigmentation program in intrinsic and acquired drug resistance is largely uncharacterized. MITF level and expression of MITF-dependent pigmentation-related genes, MLANA, PMEL, TYR, and DCT, in drug-naïve and vemurafenib- or trametinib-treated patient-derived melanoma cell lines and their drug-resistant counterparts were analysed and referred to genomic alterations. Variability in execution of pigmentation/differentiation program was detected in patient-derived melanoma cell lines. Acute treatment with vemurafenib or trametinib enhanced expression of pigmentation-related genes in MITF-M(high) melanoma cells, partially as the consequence of transcriptional reprograming. During development of resistance, changes in pigmentation program were not unidirectional, but also not universal as expression of different pigmentation-related genes was diversely affected. In selected resistant cell lines, differentiation/pigmentation was promoted and might be considered as one of drug-tolerant phenotypes. In other resistant lines, dedifferentiation was induced. Upon drug withdrawal (“drug holiday”), the dedifferentiation process in resistant cells either was enhanced but reversed by drug reexposure suggesting involvement of epigenetic mechanisms or was irreversible. The irreversible dedifferentiation might be connected with homozygous loss-of-function mutation in MC1R, as MC1R(R151C +/+) variant was found exclusively in drug-naïve MITF-M(low) dedifferentiated cells and drug-resistant cells derived from MITF(high)/MC1R(WT) cells undergoing irreversible dedifferentiation. MC1R(R151C +/+) variant might be further investigated as a parameter potentially impacting melanoma patient stratification and aiding in treatment decision. |
format | Online Article Text |
id | pubmed-6636509 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-66365092019-07-28 Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program Czyz, Malgorzata Sztiller-Sikorska, Malgorzata Gajos-Michniewicz, Anna Osrodek, Marta Hartman, Mariusz L. J Oncol Research Article Melanoma plasticity creates a plethora of opportunities for cancer cells to escape treatment. Thus, therapies must target all cancer cell subpopulations bearing the potential to contribute to disease. The role of the differentiation/pigmentation program in intrinsic and acquired drug resistance is largely uncharacterized. MITF level and expression of MITF-dependent pigmentation-related genes, MLANA, PMEL, TYR, and DCT, in drug-naïve and vemurafenib- or trametinib-treated patient-derived melanoma cell lines and their drug-resistant counterparts were analysed and referred to genomic alterations. Variability in execution of pigmentation/differentiation program was detected in patient-derived melanoma cell lines. Acute treatment with vemurafenib or trametinib enhanced expression of pigmentation-related genes in MITF-M(high) melanoma cells, partially as the consequence of transcriptional reprograming. During development of resistance, changes in pigmentation program were not unidirectional, but also not universal as expression of different pigmentation-related genes was diversely affected. In selected resistant cell lines, differentiation/pigmentation was promoted and might be considered as one of drug-tolerant phenotypes. In other resistant lines, dedifferentiation was induced. Upon drug withdrawal (“drug holiday”), the dedifferentiation process in resistant cells either was enhanced but reversed by drug reexposure suggesting involvement of epigenetic mechanisms or was irreversible. The irreversible dedifferentiation might be connected with homozygous loss-of-function mutation in MC1R, as MC1R(R151C +/+) variant was found exclusively in drug-naïve MITF-M(low) dedifferentiated cells and drug-resistant cells derived from MITF(high)/MC1R(WT) cells undergoing irreversible dedifferentiation. MC1R(R151C +/+) variant might be further investigated as a parameter potentially impacting melanoma patient stratification and aiding in treatment decision. Hindawi 2019-07-03 /pmc/articles/PMC6636509/ /pubmed/31354817 http://dx.doi.org/10.1155/2019/1697913 Text en Copyright © 2019 Malgorzata Czyz et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Czyz, Malgorzata Sztiller-Sikorska, Malgorzata Gajos-Michniewicz, Anna Osrodek, Marta Hartman, Mariusz L. Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program |
title | Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program |
title_full | Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program |
title_fullStr | Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program |
title_full_unstemmed | Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program |
title_short | Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program |
title_sort | plasticity of drug-naïve and vemurafenib- or trametinib-resistant melanoma cells in execution of differentiation/pigmentation program |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636509/ https://www.ncbi.nlm.nih.gov/pubmed/31354817 http://dx.doi.org/10.1155/2019/1697913 |
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