1. A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis.
- Author
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Guo J, Ma X, Liu D, Wang F, Xia J, Zhang B, Zhao P, Zhong F, Chen L, Long Q, Jiang L, Zhang S, Liao N, Wang J, Wu W, Sun J, Huang M, Cheng Z, Huang G, and Zou C
- Subjects
- Humans, Cell Line, Tumor, Cell Movement drug effects, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Gemcitabine pharmacology, Gemcitabine therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Prognosis, Tumor Microenvironment drug effects, Urothelium blood supply, Urothelium drug effects, Urothelium pathology, Zinc Finger E-box-Binding Homeobox 1 genetics, Zinc Finger E-box-Binding Homeobox 1 metabolism, Collagen Type IV genetics, Collagen Type IV metabolism, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition drug effects, Integrin beta1 metabolism, Integrin beta1 genetics, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic pathology, Neovascularization, Pathologic genetics, Urinary Bladder Neoplasms blood supply, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology
- Abstract
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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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