Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors
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Chowanadisai-2016-Cisplatin Resistant.pdf
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Author(s)
Chowanadisai, Winyoo
Messerli, Shanta M.
Miller, Daniel Handel
Medina, Jamie E.
Hamilton, Joshua W.
Messerli, Mark A.
Brodsky, Alexander S.
Date Issued
March 2016
Journal
PLOS ONE
Publisher
Public Library of Science
Citation
Chowanadisai, Winyoo, Shanta M. Messerli, Daniel H. Miller, Jamie E. Medina, Joshua W. Hamilton, Mark A. Messerli, and Alexander S. Brodsky. “Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.” Edited by Sandra Orsulic. PLoS ONE 11, no. 3 (March 17, 2016): e0151089.
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Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1371/journal.pone.0151089
