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A new epithelial cell subpopulation predicts response to surgery, chemotherapy, and immunotherapy in bladder cancer

ABSTRACT: The advent of neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management1-7. However, stratification of patients that would benefit most from these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single cell resolution spatial proteomic analysis of human bladder cancer to identify a novel epithelial subpopulation with therapeutic response prediction ability. These cells were defined by expression of Cadherin 12 (CDH12, N-Cadherin 2), catenins and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors had a superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offered better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherent chemoresistance mediated through ALDH1A1 expression and fibroblast activation potential. Furthermore, CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a new cancer cell population with an intriguing diametric response to the major therapeutic modalities in bladder cancer. Importantly, it also provides a compelling rationale for the design of novel biomarker guided therapeutic clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171351 | GEO | 2021/06/04

REPOSITORIES: GEO

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A new epithelial cell subpopulation predicts response to surgery, chemotherapy, and immunotherapy in bladder cancer

Project description:The advent of neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management1-7. However, stratification of patients that would benefit most from these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single cell resolution spatial proteomic analysis of human bladder cancer to identify a novel epithelial subpopulation with therapeutic response prediction ability. These cells were defined by expression of Cadherin 12 (CDH12, N-Cadherin 2), catenins and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors had a superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offered better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherent chemoresistance mediated through ALDH1A1 expression and fibroblast activation potential. Furthermore, CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a new cancer cell population with an intriguing diametric response to the major therapeutic modalities in bladder cancer. Importantly, it also provides a compelling rationale for the design of novel biomarker guided therapeutic clinical trials.

2021-06-04 | GSE169379 | GEO

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant ChemotherapyIdentification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy

Project description:Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. This project aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders.

2020-04-16 | PXD017051 | Pride

Glutathione dynamics is a potential diagnostic and therapeutic trait determining the neoadjuvant chemotherapy response to bladder cancer

Project description:Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) is a current standard care for muscle-invasive bladder cancers (MIBCs). However, the response rate remains relatively low, and current clinico-pathologic and molecular classifications are inadequate to prospectively stratify MBIC patients regarding the NAC response. Here, we showed that dysregulation in glutathione (GSH) pathway is fundamental for the NAC resistance of MBICs. Comprehensive analysis of transcriptome profiles from four independent cohorts revealed that GSH metabolism and immune response genes were significantly enriched in NAC resistant and sensitive MIBC tumors, respectively. A machine learning based tumor/stroma classifier was applied for high-throughput digitalized immunohistochemistry analysis, identifying GSH dynamic proteins including glutaminase-1 (GLS1) were associated with the NAC resistance and unfavorable clinical characteristics. Consistently, GSH dynamics was activated in cisplatin resistant human MIBC cells, stimulating their proliferation, stemness features, and invasion. Combination treatment of GSH dynamics modulators and cisplatin significantly suppressed tumor growth in an orthotopic xenograft animal model. Our results demonstrate the prognostic and therapeutic values of GSH dynamic mediators in determining the clinical features and response to NAC of patients with MIBCs.

2023-08-21 | GSE212810 | GEO

The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo

Project description:PURPOSE: Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluate the role of Aurora A, identified as an upregulated candidate molecule in bladder cancer, in regulating bladder tumor growth. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was evaluated using RNA microarray and reverse-transcriptase PCR. The specific Aurora kinase A inhibitor MLN8237 (Millennium) was used to determine effects on bladder cancer cell growth using in vitro and in vivo models using malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells. RESULTS: Urothelial carcinoma upregulates a set of 13 mitotic spindle associated transcripts, as compared to normal urothelium, including MAD2L1 (7.6-fold), BUB1B (8.8-fold), Aurora kinases A (5.6-fold) and Aurora kinase B (6.2-fold). Application of MLN8237 (10nM-1µM) to the human bladder tumor cell lines T24 and UM-UC-3 induced dose-dependent G2 cell cycle arrest, aneuploidy, mitotic spindle abnormalities, and apoptosis. MLN8237 arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model (p<0.05). Finally, in vitro combination of MLN8237 with either paclitaxel or gemcitabine produced schedule-dependent synergistic antiproliferative effects in T24 cells when administered sequentially. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma, and can be exploited with pharmacologic Aurora A inhibition. Future studies that explore the mechanisms of spindle checkpoint failure in bladder cancer and evaluate the therapeutic role of Aurora kinases for bladder cancer patients would be of value. Tissue samples with urothelial cell carcinoma from bladder as well as normal references were collected and the gene expression profiles were compared. No technical replicates.

2013-05-01 | E-GEOD-42089 | biostudies-arrayexpress

Identification of subsets of urothelial carcinoma

Project description:Identification of bladder cancer subsets 142 primary bladder tumors including superficial and invasive tumors were arrayed. 73 invasive tumors out of 142 tumors were used for muscle invasive baldder cancer classification

2014-02-10 | E-GEOD-48075 | biostudies-arrayexpress

Gene expression profiling of urothelial carcinoma

Project description:Identification of bladder cancer subsets 128 FFPE bladder tumors were used to validate the bladder cancer subsets

2014-02-10 | E-GEOD-48276 | biostudies-arrayexpress

Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

Project description:Despite cisplatin-based neoadjuvant chemotherapy (NAC) 60% of patients with muscle-invasive bladder cancer still have residual invasive disease at radical cystectomy (RC). The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. We analyzed gene expression from 133 patients with residual invasive disease after cisplatin-based NAC. H&E and immunohistochemistry were used to confirm tissue sampling and gene expression analysis. Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised consensus clustering revealed four distinct consensus clusters (CC). The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal-like and a luminal-like phenotype, respectively. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar-like subtype expressed genes associated with wound-healing/ scarring and was associated with favorable prognosis.

2019-01-01 | GSE124305 | GEO

Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival outcome to neoadjuvant chemotherapy: results from a multi-institutional validation study

Project description:Four different molecular classifications of muscle-invasive bladder cancer (MIBC) based on gene expression have been proposed. With the ultimate goal of utilizing these molecular subtypes for personalized treatment, we investigated their significance in the context of neoadjuvant cisplatin-based chemotherapy (NAC).

2017-05-25 | GSE87304 | GEO

Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer: longitudinal expression, transcriptome-level effects and modulation of chemosensitivity

Project description:Background: The response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response but has a hitherto unrecognized role in MIBC. Methods: Tumour-specific RBM3 protein expression was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients. The effect of RBM3 suppression on chemosensitivity was examined in RT4 and T24 cells in vitro. RNA-sequencing was applied to compare gene expression profiles between siRBM3-treated and control cells. Findings: RBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. High tumour-specific RBM3 expression was significantly associated with a reduced risk of recurrence in NAC treated patients. In T24 cells, which displayed higher RBM3 levels than RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. RNA-sequencing revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Interpretation: The presented data highlight the predictive value of RBM3 in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.

2022-01-11 | GSE167558 | GEO

Whole Exome Sequencing of Signet Ring/Plasmacytoid Variant Bladder Cancer

Project description:<p>In this study, six plasmacytoid bladder cancers were analyzed by whole exome sequencing. The results show loss of the CDH1 gene in every sample and correlate with E-cadherin loss of expression by immunohistochemistry. A separate validation cohort of plasmacytoid samples showed loss of E-cadherin expression by CDH1 mutation or promoter hypermethylation.</p>

| phs001064 | dbGaP

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