Project description:<p>Using whole-exome sequencing of urothelial carcinoma samples including matched sets of primary and locally recurrent or metastatic UC tumors collected over time and space and an in-depth analysis of tumors from two rapid autopsies, we provide the first detailed analysis of the therapy-driven clonal evolution of platinum-resistant urothelial carcinoma.</p> <p>We performed a systematic and integrated analyses for the molecular characterization of high-grade upper tract urothelial carcinomas (UTUC) using the whole-exome and mRNA sequencing. </p>
Project description:To identify the possible targets in EMT-acquisition after developing acquired platinum resistance in urothelial carcinoma (UC), we examined the changes in global gene expression before and after development of acquired platinum resistance. Comparing two types of acquired platinum resistant UC cells and their corresponding parent cells, in the end we identified 49 genes (25 up-regulated and 24 down-regulated genes) which were commonly changed in two acquired platinum resistant UC cells.
Project description:To identify the possible targets in EMT-acquisition after developing acquired platinum resistance in urothelial carcinoma (UC), we examined the changes in global gene expression before and after development of acquired platinum resistance. Comparing two types of acquired platinum resistant UC cells and their corresponding parent cells, in the end we identified 49 genes (25 up-regulated and 24 down-regulated genes) which were commonly changed in two acquired platinum resistant UC cells. Four invasive UC cell lines, T24, 5637, and those acquired platinum-resistant sublines T24PR and 5637PR, were used for microarrays. T24PR and 5637PR cells were newly established in our laboratory, which were grown and passaged upon reaching confluence in medium containing CDDP over a 6-month period. In preliminary studies, we found that these cell lines had an altered phenotype with morphologic and molecular changes consistent with EMT, and exhibited a marked difference in migratory potential before and after developing platinum resistance.
Project description:Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.
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: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:Purpose: The goals of this study are to compare 1. The transcription profile in KDM6A wildtype and KDM6A mutated urothelial bladder carcinoma. 2. The transcriptional changes in KDM6A mutated urothelial bladder carcinoma upon EZH2 inhibitor treatment.