Single-cell and multi-omics analyses highlight cancer-associated fibroblasts-induced immune evasion and epithelial mesenchymal transition for smoking bladder cancer

• Published in: Toxicology (Amsterdam) 2024-05, Vol.504, p.153782-153782, Article 153782
• Main Authors: Wu, Jiajin, Gao, Fang, Meng, Rui, Li, Huiqin, Mao, Zhenguang, Xiao, Yanping, Pu, Qiuyi, Du, Mulong, Zhang, Zhengdong, Shao, Qiang, Zheng, Rui, Wang, Meilin
• Format: Article
• Language: English
• Subjects: adverse outcome pathways; bladder; Bladder cancer; carcinogenesis; Epithelial-mesenchymal transition; epithelium; fibroblasts; immune evasion; Immune microenvironment; multiomics; prognosis; sequence analysis; Single-cell multi-omics analyses; tobacco; Tobacco carcinogens; toxicity; urinary bladder neoplasms
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2024.153782

Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens. •We comprehensively screened out accurate tobacco carcinogens-related genes affecting bladder cancer.•A promising tobacco carcinogens-related signature for smoking bladder cancer risk assessment and prognosis prediction.•High-risk smoking bladder cancer patients illustrated less sensitive to immunotherapy and immune evasion.•Tobacco carcinogens-induced cancer-associated fibroblasts mediated the crosstalk of EMT and immune evasion.•An AOP framework demonstrated the toxic mechanism of tobacco carcinogens in bladder cancer.