A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis

• Published in: Drug resistance updates 2024-09, Vol.76, p.101116, Article 101116
• Main Authors: Guo, Jinan, Ma, Xiaoshi, Liu, Dongcheng, Wang, Fei, Xia, Jinquan, Zhang, Bin, Zhao, Pan, Zhong, Fuhua, Chen, Lipeng, Long, Qiaoyun, Jiang, Lu, Zhang, Siyu, Liao, Naikai, Wang, Jigang, Wu, Weiqing, Sun, Jichao, Huang, Mou, Cheng, Zhiqiang, Huang, Guixiao, Zou, Chang
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Movement - drug effects; Chemotherapy resistance and recurrence; COL4A1-ITGB1 Interaction; Collagen Type IV - genetics; Collagen Type IV - metabolism; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition - drug effects; Gemcitabine - pharmacology; Gemcitabine - therapeutic use; Gene Expression Regulation, Neoplastic - drug effects; Humans; Integrin beta1 - genetics; Integrin beta1 - metabolism; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Prognosis; Single-cell RNA sequencing; Tumor microenvironment; Tumor Microenvironment - drug effects; Urinary Bladder Neoplasms - blood supply; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urothelial carcinoma; Urothelium - blood supply; Urothelium - drug effects; Urothelium - pathology; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 1368-7646; 1532-2084; 1532-2084
• DOI: 10.1016/j.drup.2024.101116

Drug resistance and tumor recurrence remain clinical challenges in the treatment of urothelial carcinoma (UC). However, the underlying mechanism is not fully understood. Here, we performed single-cell RNA sequencing and identified a subset of urothelial cells with epithelial-mesenchymal transition (EMT) features (EMT-UC), which is significantly correlated with chemotherapy resistance and cancer recurrence. To validate the clinical significance of EMT-UC, we constructed EMT-UC like cells by introducing overexpression of two markers, Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Desmin (DES), and examined their histological distribution characteristics and malignant phenotypes. EMT-UC like cells were mainly enriched in UC tissues from patients with adverse prognosis and exhibited significantly elevated EMT, migration and gemcitabine tolerance in vitro. However, EMT-UC was not specifically identified from tumorous tissues, certain proportion of them were also identified in adjacent normal tissues. Tumorous EMT-UC highly expressed genes involved in malignant behaviors and exhibited adverse prognosis. Additionally, tumorous EMT-UC was associated with remodeled tumor microenvironment (TME), which exhibited high angiogenic and immunosuppressive potentials compared with the normal counterparts. Furthermore, a specific interaction of COL4A1 and ITGB1 was identified to be highly enriched in tumorous EMT-UC, and in the endothelial component. Targeting the interaction of COL4A1 and ITGB1 with specific antibodies significantly suppressed tumorous angiogenesis and alleviated gemcitabine resistance of UC. Overall, our findings demonstrated that the driven force of chemotherapy resistance and recurrence of UC was EMT-UC mediated COL4A1-ITGB1 interaction, providing a potential target for future UC treatment. [Display omitted] •An EMT-featured urothelial subset with significant correlation to poor prognosis in urothelial carcinoma was identified by scRNA-seq.•EMT-UC like cells constructed by overexpression of ZEB1 and DES showed significantly elevated EMT, migration and gemcitabine tolerance.•Tumorous EMT-UC remodeled the TME into immunosuppressive and high angiogenic environments to facilitate tumor progression.•COL4A1-ITGB1 was identified highly enriched in tumorous EMT-UC with TME, particularly with the endothelial component.•Specific blockade of COL4A1-ITGB1 significantly suppressed tumorous angiogenesis and gemcitabine-resistant UC progression.