Project description:Resistance to platinum compounds represents a major obstacle to the cure of ovarian carcinoma. The molecular profiling of drug-sensitive and drug-resistant cells may be helpful to clarify if altered gene expression can contribute to the drug-resistant phenotype. The expression pattern of three ovarian carcinoma cell lines was examined. The analysis revealed the modulation of several genes in the two platinum-resistant cell lines as compared to parental platinum-sensitive cells. The integration of the information obtained through gene expression analysis may be useful to clarify the specific molecular alterations of factors and pathway favouring survival of tumor cells.
Project description:Resistance to platinum compounds represents a major obstacle to the cure of ovarian carcinoma. The molecular profiling of drug-sensitive and drug-resistant cells may be helpful to clarify if altered expression of miRNAs can contribute to the drug-resistant phenotype. The expression pattern of miRNAs of three ovarian carcinoma cell lines was examined. The analysis revealed the modulation of several miRNAs in the two platinum-resistant cell lines as compared to parental platinum-sensitive cells. The integration of the information obtained through miRNA expression analysis may be useful to clarify the specific molecular alterations of factors and pathway favouring survival of tumor cells.
Project description:Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making as of yet. Two particular challenges faced in mechanistically deciphering platinum responsiveness in ovarian cancer have been the suitability of cell line models for ovarian cancer subtypes and the availability of information on comparatively how sensitive ovarian cancer cell lines are to platinum. We performed one of the most comprehensive profiles to date on 36 ovarian cancer cell lines across over seven subtypes and integrated drug response and multiomic data to improve on our understanding of the best cell line models for platinum responsiveness in ovarian cancer. RNAseq analysis of the 36 cell lines in a single batch experiment largely conform with the currently accepted subtyping of ovarian cancers, further supporting other studies that demonstrate that commonly used cell lines are poor models of high-grade serous ovarian carcinoma. We performed drug dose response assays in the 32 of these cell lines for cisplatin and carboplatin, as previous studies have not comprehensively reported this quantity of cell lines and/or the actual IC50s for these drugs. Our results demonstrate that cell lines largely fall either well above or below the equivalent dose of the clinical maximally achievable dose (Cmax) of each compound, allowing designation of cell lines as sensitive or resistant. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines to identify gene expression correlating with platinum-response. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4, as well as leveraged clinically-resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models to perform differential expression analysis for seven total isogenic pairs of platinum resistant cell lines. While gene expression changes overall were heterogeneous and vast, themes of innate immunity/STAT activation, epithelial to mesenchymal transition and stemness, and platinum influx/efflux regulators. In addition to gene expression analyses, we performed copy number signature analysis and orthogonal measures of HRD scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines, which revealed unique features of some ovarian cancer models. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness feature contributions to platinum resistance, as this is likely a transient state. Overall this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.
Project description:Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making as of yet. Two particular challenges faced in mechanistically deciphering platinum responsiveness in ovarian cancer have been the suitability of cell line models for ovarian cancer subtypes and the availability of information on comparatively how sensitive ovarian cancer cell lines are to platinum. We performed one of the most comprehensive profiles to date on 36 ovarian cancer cell lines across over seven subtypes and integrated drug response and multiomic data to improve on our understanding of the best cell line models for platinum responsiveness in ovarian cancer. RNAseq analysis of the 36 cell lines in a single batch experiment largely conform with the currently accepted subtyping of ovarian cancers, further supporting other studies that demonstrate that commonly used cell lines are poor models of high-grade serous ovarian carcinoma. We performed drug dose response assays in the 32 of these cell lines for cisplatin and carboplatin, as previous studies have not comprehensively reported this quantity of cell lines and/or the actual IC50s for these drugs. Our results demonstrate that cell lines largely fall either well above or below the equivalent dose of the clinical maximally achievable dose (Cmax) of each compound, allowing designation of cell lines as sensitive or resistant. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines to identify gene expression correlating with platinum-response. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4, as well as leveraged clinically-resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models to perform differential expression analysis for seven total isogenic pairs of platinum resistant cell lines. While gene expression changes overall were heterogeneous and vast, themes of innate immunity/STAT activation, epithelial to mesenchymal transition and stemness, and platinum influx/efflux regulators. In addition to gene expression analyses, we performed copy number signature analysis and orthogonal measures of HRD scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines, which revealed unique features of some ovarian cancer models. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness feature contributions to platinum resistance, as this is likely a transient state. Overall this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.
Project description:Ovarian cancer is one of the leading causes of death in females in the world. High-grade serous ovarian carcinoma (HGSOC) is the most common histological subtype, and platinum platinum-resistance is a clinical challenge, In this study, we investigated the gene expression profiles of platinum-resistant and platinum-sensitive HGSOC.
Project description:To determine the signaling networks that are dysregulated in platinum-resistant ovarian cancer, gene expression data were obtained from, and compared between, the ovarian cancer cell line, A2780, and its cisplatin-resistant derivative, A2780cis. Gene expression data from a cisplatin-sensitive ovarian cancer cell line (A2780) were collected and compared to gene expression data from a cisplatin-resistant cell line (A2780cis). 6 independent experiments were completed for both the sensitive and resistant cell lines.
Project description:Ovarian cancer is one of the leading causes of death in females in the world. High-grade serous ovarian carcinoma (HGSOC) is the most common histological subtype, and the platinum-resistance is a clinical challenge, In this study, we investigated the microRNA (miRNA) profiles of platinum-resistant and platinum-sensitive HGSOC.