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Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors

The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian...

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Autores principales: Chowanadisai, Winyoo, Messerli, Shanta M., Miller, Daniel H., Medina, Jamie E., Hamilton, Joshua W., Messerli, Mark A., Brodsky, Alexander S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795743/
https://www.ncbi.nlm.nih.gov/pubmed/26986722
http://dx.doi.org/10.1371/journal.pone.0151089
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author Chowanadisai, Winyoo
Messerli, Shanta M.
Miller, Daniel H.
Medina, Jamie E.
Hamilton, Joshua W.
Messerli, Mark A.
Brodsky, Alexander S.
author_facet Chowanadisai, Winyoo
Messerli, Shanta M.
Miller, Daniel H.
Medina, Jamie E.
Hamilton, Joshua W.
Messerli, Mark A.
Brodsky, Alexander S.
author_sort Chowanadisai, Winyoo
collection PubMed
description The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.
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spelling pubmed-47957432016-03-23 Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors Chowanadisai, Winyoo Messerli, Shanta M. Miller, Daniel H. Medina, Jamie E. Hamilton, Joshua W. Messerli, Mark A. Brodsky, Alexander S. PLoS One Research Article The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition. Public Library of Science 2016-03-17 /pmc/articles/PMC4795743/ /pubmed/26986722 http://dx.doi.org/10.1371/journal.pone.0151089 Text en © 2016 Chowanadisai et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chowanadisai, Winyoo
Messerli, Shanta M.
Miller, Daniel H.
Medina, Jamie E.
Hamilton, Joshua W.
Messerli, Mark A.
Brodsky, Alexander S.
Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
title Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
title_full Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
title_fullStr Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
title_full_unstemmed Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
title_short Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
title_sort cisplatin resistant spheroids model clinically relevant survival mechanisms in ovarian tumors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795743/
https://www.ncbi.nlm.nih.gov/pubmed/26986722
http://dx.doi.org/10.1371/journal.pone.0151089
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