title: Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.
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.
authors.affiliation: Department of Nutritional Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America, 74078.|Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 02543.
authors.forename: Winyoo
authors.initials: W
authors.lastname: Chowanadisai
authors.affiliation: Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 02543.
authors.forename: Shanta M
authors.initials: SM
authors.lastname: Messerli
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 02139.|Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America, 02142.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Miller
authors.affiliation: Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 02543.|Department of Biological Sciences, Bridgewater State University, Bridgewater, Massachusetts, United States of America, 02325.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Medina
authors.affiliation: Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 02543.|Swenson College of Science and Engineering, University of Minnesota, Duluth, Minnesota, United States of America, 55804.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Hamilton
authors.affiliation: Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 02543.|Department of Biology and Microbiology, South Dakota State University, Brookings, South Dakota, United States of America, 57007.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Messerli
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 02139.|Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island, United States of America, 02903.|Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, United States of America, 02912.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin