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.
Project description:The bladder urothelium is a stratified epithelium, categorized as basal, intermediate, and umbrella cells. While epithelial–mesenchymal transition is known to occur during bladder injury, regeneration, and sarcomatoid tumor formation, it remains unclear whether normal urothelial cells intrinsically possess a mesenchymal-like epithelial state. We analyzed scRNA-seq data of EPCAM+ urothelial cells from both mouse and human urothelium. Vimentin-positive cells were evaluated by immunostaining to determine their distribution in normal urothelial layers and sarcomatoid tumors. Here, we identified and characterized a rare population of mesenchymal-like urothelial cells, termed M-cells, representing ~1–3% of urothelial cells. M-cells co-express epithelial markers with mesenchymal and stemness genes and engage stem-associated transcriptional regulators. Lineage tracing with the Upk2-Cre mT/mG reporter mice confirmed their urothelial origin, excluding a fibroblast lineage. M-cells are enriched within the basal layer but present across all urothelial compartments. M-cells exhibit high transcriptional plasticity between basal cells and intermediate cells. In addition, we identified a 16-gene transcriptional signature uniquely expressed in M-cells but absent in fibroblasts. RNA deconvolution of MB49 tumors demonstrated strong enrichment of this signature, suggesting that MB49 tumors are more likely to represent sarcomatoid urothelial carcinoma rather than fibroblast-derived sarcoma. The clinical relevance of M-cells and the M-cell state was validated in primary human sarcomatoid tumors and their corresponding patient-derived xenografts. Together, these findings establish transcriptionally unique and rare mesenchymal-like cells within the normal urothelium as a novel highly plastic population with translational implications for both mouse and human sarcomatoid urothelial carcinoma.
Project description:HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. While HER2-directed therapies like fam-trastuzumab deruxtecan (T-DXd) are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer (PC) and urothelial carcinoma (UC) remains inadequately characterized.This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer.
Project description:Urine cytologic examination is a widely used primary pathologic screening test in the diagnosis of bladder urothelial carcinoma (BLCA), however the low diagnostic accuracy remains challenging. We conducted high-throughput proteome on ten pairs of BLCA and benign urothelial lesion (BUL) to identify a supportive proteomic marker as an ancillary test in liquid based cytology (LBC).
Project description:The bladder urothelium is a stratified epithelium, categorized as basal, intermediate, and umbrella cells. While epithelial–mesenchymal transition is known to occur during bladder injury, regeneration, and sarcomatoid tumor formation, it remains unclear whether normal urothelial cells intrinsically possess a mesenchymal-like epithelial state. We analyzed scRNA-seq data of EPCAM+ urothelial cells from both mouse and human urothelium. Vimentin-positive cells were evaluated by immunostaining to determine their distribution in normal urothelial layers and sarcomatoid tumors. Here, we identified and characterized a rare population of mesenchymal-like urothelial cells, termed M-cells, representing ~1–3% of urothelial cells. M-cells co-express epithelial markers with mesenchymal and stemness genes and engage stem-associated transcriptional regulators. Lineage tracing with the Upk2-Cre mT/mG reporter mice confirmed their urothelial origin, excluding a fibroblast lineage. M-cells are enriched within the basal layer but present across all urothelial compartments. M-cells exhibit high transcriptional plasticity between basal cells and intermediate cells. In addition, we identified a 16-gene transcriptional signature uniquely expressed in M-cells but absent in fibroblasts. RNA deconvolution of MB49 tumors demonstrated strong enrichment of this signature, suggesting that MB49 tumors are more likely to represent sarcomatoid urothelial carcinoma rather than fibroblast-derived sarcoma. The clinical relevance of M-cells and the M-cell state was validated in primary human sarcomatoid tumors and their corresponding patient-derived xenografts. Together, these findings establish transcriptionally unique and rare mesenchymal-like cells within the normal urothelium as a novel highly plastic population with translational implications for both mouse and human sarcomatoid urothelial carcinoma.
Project description:Urothelial carcinoma of the bladder, the second most prevalent cancer within the urothelial system, often evades immune recognition by natural killer (NK) cells, but studies have shown that cyproheptadine (CPH), an anti-histamine drug, exhibits anticancer effects in this carcinoma. Co-culturing CPH-treated cells with NKG2D-expressing NK92 cells resulted in enhanced NK-mediated lysis of UC cells, with RNA-seq analysis revealing increased expression of the NKG2D ligand ULBP2 in CPH-treated cells. We hypothesize that cyproheptadine as a epigenetic modifier enhances NK-mediated cytotoxicity by restoring NKG2D ligands and CCL3 and as a control we used entinostat a known FDA approved HDAC1/3 inhibitor. Targeting NK cells offers a promising strategy against urothelial carcinoma. Further analysis showed epigenetic regulation of ULBP2 expression with increased H3K27Ac active mark enrichment in CPH-treated cells. Overexpression of ULBP2 led to increased NK-mediated lysis, while knockdown reduced it in CPH-treated urothelial carcinoma cells. Additionally, CPH treatment enhanced the anti-tumor effect in a mouse model, likely due to increased NK and NKT cell infiltration. In summary, CPH triggers an innate immune response against urothelial carcinoma by promoting NK cell-mediated cytotoxicity through ULBP2 and CCL3 restoration.
Project description:This SuperSeries is composed of the following subset Series: GSE32535: Integrated genomic and gene expression profiling identifies two major gene/genomic circuits operating in urothelial carcinoma (genomic) GSE32548: Integrated genomic and gene expression profiling identifies two major gene/genomic circuits operating in urothelial carcinoma (gene expression) Refer to individual Series