TY - JOUR
T1 - Cisplatin resistant spheroids model clinically relevant survival mechanisms in ovarian tumors
AU - Chowanadisai, Winyoo
AU - Messerli, Shanta M.
AU - Miller, Daniel H.
AU - Medina, Jamie E.
AU - Hamilton, Joshua W.
AU - Messerli, Mark A.
AU - Brodsky, Alexander S.
N1 - Funding Information:
This work was funded by the National Institutes of Health (NIH) NCRR supplement grant P41 RR001395-27S1 (JWH), National Science Foundation (NSF) DBI-1005378 “REU Site: Biological Discovery in Woods Hole”, faculty startup funds from the Office of Research at Oklahoma State University (WC), and the Mary Kay Foundation (ASB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Joel Commisso at the Interdisciplinary Center for Plasma Mass Spectrometry at the University of California, Davis, for his technical expertise. We thank Milton C. Gum for his advice regarding dataset analyses. This work was funded by the NIH NCRR supplement grant P41 RR001395-27S1 (J.W.H.), NSF DBI-1005378 “REU Site: Biological Discovery in Woods Hole”, faculty startup funds from the Office of Research at Oklahoma State University (W.C.), and the Mary Kay Foundation (A.S.B.).
Funding Information:
Funding: This work was funded by the National Institutes of Health (NIH) NCRR supplement grant P41 RR001395-27S1 (JWH), National Science Foundation (NSF) DBI-1005378 “REU Site: Biological Discovery in Woods Hole”, faculty startup funds from the Office of Research at Oklahoma State University (WC), and the Mary Kay Foundation (ASB). The funders had no role in study design, data collection
Funding Information:
We thank Joel Commisso at the Interdisciplinary Center for Plasma Mass Spectrometry at the University of California, Davis, for his technical expertise. We thank Milton C. Gum for his advice regarding dataset analyses. This work was funded by the NIH NCRR supplement grant P41 RR001395-27S1 (J.W.H.), NSF DBI-1005378 “REU Site: Biological Discovery in Woods Hole”, faculty startup funds from the Office of Research at Oklahoma State University (W.C.), and the Mary Kay Foundation (A.S.B.).
Publisher Copyright:
© 2016 Chowanadisai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0151089
DO - 10.1371/journal.pone.0151089
M3 - Article
C2 - 26986722
AN - SCOPUS:84994790568
SN - 1932-6203
VL - 11
JO - PLoS One
JF - PLoS One
IS - 3
M1 - e0151089
ER -