Characterization of three Epithelial Ovarian Cancer cell lines resistant to cisplatin (mRNA).
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE93793 | GEO | 2017/07/24
SECONDARY ACCESSION(S): PRJNA362360
REPOSITORIES: GEO
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Project description:Epithelial ovarian cancer (EOC) represents the gynecologic cancer with the highest mortality rate. Despite a high initial response to chemotherapy, the majority of patients with advanced EOC relapses and subsequently develops chemoresistance that results in treatment failure and death of the patient. AIM: we have generated an isogenic model of PT-resistance in a panel of 3 EOC cell lines. microRNA profiling was used to identify new molecular pathway that regulate chemoresistance.
2017-07-24 | GSE93794 | GEO
Project description:Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death. Despite many patients achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. We assessed whether antibiotic (ABX) therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or ABX containing water (metronidazole, ampicillin, vancomycin, and neomycin) before being intraperitoneally injected with murine EOC cells. Stool was collected to confirm microbiome disruption and tumors were monitored, and cisplatin therapy was administered weekly until endpoint. EOC tumor-bearing mice demonstrate accelerated tumor growth and resistance to cisplatin therapy in ABX treated compared with nonABX treatment. Stool analysis indicated most gut microbial species were disrupted by ABX treatment except for ABX resistant bacteria. To test for role of the gut microbiome, cecal microbiome transplants (CMTs) of microbiota derived from ABX or nonABX treated mice were used to recolonize the microbiome of ABX treated mice. nonABX cecal microbiome was sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut derived tumor suppressor. Mechanistically, tumors from ABX treated compared to nonABX treated mice contained a high frequency of cancer stem cells that were augmented by cisplatin. These studies indicate an intact microbiome provides a gut derived tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment.
2022-11-01 | GSE200025 | GEO
Project description:Essentially, all patients diagnosed with ovarian cancer (OC) are treated with platinum (Pt); however, Pt resistance (Pt-R) rapidly develops. We show OC cells resistant to Pt increase intracellular cholesterol by increasing expression of the high-density lipoprotein (HDL) receptor, scavenger receptor class B type 1 (SR-B1). Expression of SR-B1 was associated with chemoresistance in OC cells and tumors. SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death of Pt-R OC cells in vitro and suppressed Pt-R OC tumor growth in vivo. Reduced cholesterol accumulation in Pt-R OC cells induced lipid oxidative stress through reduction of glutathione peroxidase 4 (GPx4) expression leading to ferroptosis. Reduction of GPx4 expression in OC cells re-sensitized Pt-R cells to Pt by reducing cholesterol uptake and enhancing the accumulation of lipid reactive oxygen species (L-ROS). Mechanistically, GPx4 knockdown in OC cells was associated with reduced expression of the histone acetyltransferase EP300, leading to reduced H3K27 acetylation around the SREBP2 promoter suppressing its expression. As SREBP2 regulates SR-B1 transcription, these data demonstrate chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBP2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.
2024-06-01 | GSE234404 | GEO
Project description:We profile expression in serous epithelial ovarian carcinomas to assess the possibility of an miRNA signature associated with chemoresistance. Resistance to the available therapies is one of the main causes of low survival of patients with advanced epithelial ovarian cancer, thus representing an emergency in oncology. Here, we profiled miRNA expression in 86 naïve serous epithelial ovarian carcinomas (EOCs) to assess the possibility of miRNAs associated with chemoresistance. We identified 23 miRNAs associated with chemoresistance, of which three (miR-484, miR-642 and miR-217) were confirmed in the validation set (112 independent patients). The study of miR-484 role demonstrated that it regulated the chemoresistance of EOC cells acting not on cancer cells but on tumor vasculature. In particular, miR-484 is produced and secreted by chemosensitive EOC, therefore regulating the production of VEGFB by cancer cells and the expression of VEGFR2 in endothelial cells. Overall, we demonstrated that a three-miR signature can classify the response to chemotherapy and that chemoresistance in EOC relays, at least in part, on the control of tumor angiogenesis, indicating new options in the treatment of these patients. We analyzed tumor samples (<5% of normal tissue) from FFPE blocks of 86 patients with serous ovarian carcinomas.
2013-05-17 | E-GEOD-43867 | biostudies-arrayexpress
Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC provided benefit in <15% of patients. EOC is a particularly complex cancer since it develops from various tissues in the reproductive tract and metastasizes into the peritoneal cavity where it is able to colonize almost all organs, creating different tumor microenvironments (TME) containing a variety of immune profiles. In this study, we assessed the immune composition of different murine syngeneic models of EOC from different cellular origins (ovarian and fallopian tube epithelium) and harboring known mutations relevant to human disease, including TP53 mutation, PTEN suppression, and constitutive KRAS activation. We determined immunogenicity of multiple tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition of ascites, by flow cytometry, IHC and single cell RNA-sequencing. Our findings allowed us to predict which models might respond best to PD-L1 blockage, according to key characteristics such as tumor immunogenicity, MHC status, and T cell infiltration. Together these data highlight the heterogeneity found in murine EOC, as in human disease, identified features that might predict immune checkpoint inhibitor efficacy, and revealed crucial information about differences between murine models in the TME composition vs. ascites fluid. These data provide a solid foundation for selecting models in future testing of immunotherapies according to the immune composition and tumor characteristics.
2022-06-01 | GSE183368 | GEO
Project description:We profile expression in serous epithelial ovarian carcinomas to assess the possibility of an miRNA signature associated with chemoresistance. Resistance to the available therapies is one of the main causes of low survival of patients with advanced epithelial ovarian cancer, thus representing an emergency in oncology. Here, we profiled miRNA expression in 86 naïve serous epithelial ovarian carcinomas (EOCs) to assess the possibility of miRNAs associated with chemoresistance. We identified 23 miRNAs associated with chemoresistance, of which three (miR-484, miR-642 and miR-217) were confirmed in the validation set (112 independent patients). The study of miR-484 role demonstrated that it regulated the chemoresistance of EOC cells acting not on cancer cells but on tumor vasculature. In particular, miR-484 is produced and secreted by chemosensitive EOC, therefore regulating the production of VEGFB by cancer cells and the expression of VEGFR2 in endothelial cells. Overall, we demonstrated that a three-miR signature can classify the response to chemotherapy and that chemoresistance in EOC relays, at least in part, on the control of tumor angiogenesis, indicating new options in the treatment of these patients.
2013-05-17 | GSE43867 | GEO
Project description:Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the US. Ovarian cancer stem cells (OCSCs) have been shown to drive chemoresistance and tumor progression but the mechanism remains incompletely understood. Aldehyde Dehydrogenase 1A1 (ALDH1A1) is a robust marker for cancer stem cells in ovarian and other cancers. We demonstrate that ALDH1A1 inhibition suppresses stemness, chemoresistance and senescence in ovarian cancer.
2022-08-03 | GSE200641 | GEO
Project description:The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). Experimental design: Fluorescence in situ hybridization and immunochemistry were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/β-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/β-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1 and NFAT5 was explored using CLIP-seq (PRJNA484809), RIP, electrophoretic mobility shift and immunoblotting immunofluorescence assays. Results: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited β-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1 and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, co-therapy of CBP/β-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. Conclusions: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.
2018-11-06 | GSE122146 | GEO
Project description:The goal of the study was to identify molecular subgroups that might predict clinical outcomes in serous epithelial ovarian cancer (EOC) patients. A second objective was to identify potential therapeutic targets for serous EOC based on improved understanding of the molecular diversity of the disease. Ovarian tissues and matched peripheral blood samples were prospectively obtained from sequential patients undergoing planned gynecologic surgery at Cedars-Sinai Medical Center between 1989 and 2005. All patients underwent surgery and received adjuvant chemotherapy with a contemporaneous standard-of-care regimen. Ovarian tissue samples (n=172) were compared to a reference pool of 106 ovarian samples. Mixed reference includes normal, benign, borderline, and malignant samples.
2013-12-26 | E-GEOD-51088 | biostudies-arrayexpress
Project description:The goal of the study was to identify molecular subgroups that might predict clinical outcomes in serous epithelial ovarian cancer (EOC) patients. A second objective was to identify potential therapeutic targets for serous EOC based on improved understanding of the molecular diversity of the disease. Ovarian tissues and matched peripheral blood samples were prospectively obtained from sequential patients undergoing planned gynecologic surgery at Cedars-Sinai Medical Center between 1989 and 2005. All patients underwent surgery and received adjuvant chemotherapy with a contemporaneous standard-of-care regimen.
2013-12-26 | GSE51088 | GEO