Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors

Winyoo Chowanadisai, Shanta M. Messerli, Daniel H. Miller, Jamie E. Medina, Joshua W. Hamilton, Mark A. Messerli, Alexander S. Brodsky

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e0151089
JournalPloS one
Volume11
Issue number3
DOIs
StatePublished - Jan 1 2016

Fingerprint

cisplatin
ovarian neoplasms
Cisplatin
Tumors
Survival
Gene expression
Neoplasms
Genes
Cells
Ovarian Neoplasms
gene expression
cell lines
Transcriptome
Cell Line
Epithelial-Mesenchymal Transition
genes
drug resistance
Gene Expression Profiling
resistance mechanisms
lethal genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chowanadisai, W., Messerli, S. M., Miller, D. H., Medina, J. E., Hamilton, J. W., Messerli, M. A., & Brodsky, A. S. (2016). Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors. PloS one, 11(3), e0151089. https://doi.org/10.1371/journal.pone.0151089

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.

In: PloS one, Vol. 11, No. 3, 01.01.2016, p. e0151089.

Research output: Contribution to journalArticle

Chowanadisai, W, Messerli, SM, Miller, DH, Medina, JE, Hamilton, JW, Messerli, MA & Brodsky, AS 2016, 'Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors', PloS one, vol. 11, no. 3, pp. e0151089. https://doi.org/10.1371/journal.pone.0151089
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. In: PloS one. 2016 ; Vol. 11, No. 3. pp. e0151089.
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