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Tumor Stemness Score to Estimate Epithelial-to-Mesenchymal Transition (EMT) and Cancer Stem Cells (CSCs) Characterization and to Predict the Prognosis and Immunotherapy Response in Bladder Urothelial Carcinoma

ABSTRACT: Background: The relationships between cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment (TME) in bladder urothelial carcinoma (BLCA) remain unclear. Methods: We first constructed tumor stemness (TS) score using principal component analysis to quantify tumor stemness in BLCA. Then, we evaluated the clinical value of the TS score for predicting the response to tumor immunotherapy using immunotherapy cohorts. Finally, we built an EMT cell model by treating T24 cells with TGF-β and validated the relationship between the TS score and the EMT process in tumors by real-time quantitative PCR, cell invasion assays, and RNA-seq. Results: A TS scoring system was established with 61 TS-related genes to quantify the TS. The prognostic value of the TS score was then confirmed in multiple independent cohorts. A high TS score was associated with high EMT activity, CSC characteristics, high stromal cell content, high TP53 mutation rate, poor prognosis, and high tumor immunotherapy tolerance. Conclusion: The TS score provides an index for EMT and CSC research and helps clinicians develop treatment plans and predict outcomes for patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215947 | GEO | 2022/10/21

REPOSITORIES: GEO

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Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common malignant pancreatic tumor in western countries, characterized by a low 5-year survival rate of only 11 %. Owing to a lack of early and specific symptoms, most patients are diagnosed at advanced or even me-tastasized stages essentially impairing treatment efficacy. Metastatic outgrowth requires a high plasticity of tumor cells implying phenotypic switching in response to changing envi-ronments. One important process leading to phenotypic switching is the Epithelial-Mesenchymal-Transition (EMT) and its reversion, the Mesenchymal-Epithelial-Transition (MET). This process has been associated with the gain of cancer stem cell (CSC) properties being regarded as drivers of tumor initiation at primary and secondary sites. Still, it is poorly understood whether different CSC phenotypes exist along the EMT/MET axis and how these impact malignancy associated properties. Thus, this study aimed to characterize CSC popula-tions of epithelial and mesenchymal PDAC cells and how these relate to functional pheno-types. Methods: For this purpose, single-cell-cloning of the two PDAC cell lines Panc1 and Panc89 was performed to isolate and expand CSC- (Holoclone cells) and non-CSC (Paraclone cells) clones. Cell variants were characterized regarding cell growth, migration, invasion, cell ad-hesion and tumorigenicity. Results: Panc1 Holoclone cells showed a mesenchymal phenotype dominated by high ex-pression of the stemness marker Nestin, while Panc89 Holoclone cells exhibited an epitheli-al phenotype with elevated expression of the stemness marker SOX2. Moreover, Panc89 Holoclone cells showed enhanced cell growth and colony formation ability compared to Panc1 Holoclone cells. In contrast, slowly proliferating Panc1 Holoclone cells were highly invasive, while Panc89 Holoclone cells showed a slow cluster-like invasion. In line with these findings, a higher number of metastases was formed by Panc1 Holoclone cells in vivo. How-ever, Panc89 Holoclone cells led to formation of larger tumors limiting survival of inoculated mice. Moreover, epithelial and mesenchymal CSC-clones showed clear differences with re-spect to organ manifestation. Conclusion: Overall, these data support the view of different CSC phenotypes in PDAC cells that are linked to distinct EMT/MET phenotypes and that manifest in a different metastatic propensity.

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Tumor Stemness Score to Estimate Epithelial-to-Mesenchymal Transition (EMT) and Cancer Stem Cells (CSCs) Characterization and to Predict the Prognosis and Immunotherapy Response in Bladder Urothelial Carcinoma

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