Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis

• Published in: Cell reports (Cambridge) Vol. 43; no. 5; p. 114146
• Main Authors: Lee, Sangkyou, Bondaruk, Jolanta, Wang, Yishan, Chen, Huiqin, Lee, June Goo, Majewski, Tadeusz, Mullen, Rachel D., Cogdell, David, Chen, Jiansong, Wang, Ziqiao, Yao, Hui, Kus, Pawel, Jeong, Joon, Lee, Ilkyun, Choi, Woonyoung, Navai, Neema, Guo, Charles, Dinney, Colin, Baggerly, Keith, Mendelsohn, Cathy, McConkey, David, Behringer, Richard R., Kimmel, Marek, Wei, Peng, Czerniak, Bogdan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-05-2024; Elsevier
• Subjects: Aged; Aged, 80 and over; Animals; bladder cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Differentiation; CP: Cancer; Female; field carcinogenesis; field effects; forerunner genes; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; mucosal microenvironment; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; urothelial differentiation; Urothelium - metabolism; Urothelium - pathology; mucosal microenvironment; field carcinogenesis; field effects; bladder cancer; CP: Cancer; forerunner genes; urothelial differentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114146

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term “forerunner” genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.
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•Silencing of FR genes is associated with mucosal field effects in bladder carcinogenesis•LPAR6 and CAB39L are distinctively downregulated in luminal and basal bladder cancers•Effects of LPAR6 and CAB39L are mediated by cholesterol and the unfolded protein reaction•LPAR6 and CAB39L loss dysregulates urothelial differentiation, contributing to carcinogenesis
Lee et al. report that FR genes mapping near RB1 are associated with the development of field effects initiating bladder carcinogenesis. Two of these genes are distinctively downregulated in luminal and basal cancers. Their loss contributes to carcinogenesis by dysregulating urothelial differentiation mediated by cholesterol and the unfolded protein reaction.