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

Guo, Jinan1; Ma, Xiaoshi2; Liu, Dongcheng1,3; Wang, Fei4; Xia, Jinquan1; Zhang, Bin1; Zhao, Pan1; Zhong, Fuhua1; Chen, Lipeng1; Long, Qiaoyun1; Jiang, Lu1; Zhang, Siyu1; Liao, Naikai5; Wang, Jigang1; Wu, Weiqing1; Sun, Jichao1; Huang, Mou6; Cheng, Zhiqiang1; Huang, Guixiao6; Zou, Chang7

2024-09-01

10.1016/j.drup.2024.101116

DRUG RESISTANCE UPDATES   影响因子和分区

1368-7646

1532-2084

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.

Urothelial carcinoma Single -cell RNA sequencing Tumor microenvironment Chemotherapy resistance and recurrence

SCI

英语

第一 ; 通讯

National Natural Science Foundation of China[82303339] ; Guangdong Provincial Natural Science Foundation[2021A1515010919] ; Basic and Applied Basic Research Foundation of Guangdong Province[2021A1515111144] ; Medical Scientific Research Foundation of Guangdong Province[B2021310] ; Shenzhen Key Medical Discipline Construction Fund["SZXK053","SZXK055"] ; Science and Technology Foundation of Shenzhen["JCYJ20210324115800001","JCYJ20210324113008020","JCYJ202205 30152405011"] ; Shenzhen People's Hospital Physician Scientist Training "Five Three" Program[SYWGSLCYJ202302]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:001265568600001

CHURCHILL LIVINGSTONE

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 2, Shenzhen, Guangdong, Peoples R China
3.Shenzhen Aier Eye Hosp, Shenzhen, Guangdong, Peoples R China
4.Hainan Med Univ, Hainan Affiliated Hosp, Hainan Gen Hosp, Haikou, Hainan, Peoples R China
5.Guangxi Med Univ, Affiliated Hosp 1, Nanning, Guangxi, Peoples R China
6.Shenzhen Univ, Affiliated Hosp 3, Shenzhen, Guangdong, Peoples R China
7.Chinese Univ Hong Kong Shenzhen, Shenzhen, Guangdong, Peoples R China

Guo, Jinan,Ma, Xiaoshi,Liu, Dongcheng,et al. A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis[J]. DRUG RESISTANCE UPDATES,2024,76.

Guo, Jinan.,Ma, Xiaoshi.,Liu, Dongcheng.,Wang, Fei.,Xia, Jinquan.,...&Zou, Chang.(2024).A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis.DRUG RESISTANCE UPDATES,76.

Guo, Jinan,et al."A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis".DRUG RESISTANCE UPDATES 76(2024).