Lee, SangkyouBondaruk, JolantaWang, YishanChen, HuiqinLee, June GooMajewski, TadeuszMullen, Rachel D.Cogdell, DavidChen, JiansongWang, ZiqiaoYao, HuiKus, PawelJeong, JoonLee, IlkyunChoi, WoonyoungNavai, NeemaGuo, CharlesDinney, ColinBaggerly, KeithMendelsohn, CathyMcConkey, DavidBehringer, Richard R.Kimmel, MarekWei, PengCzerniak, Bogdan2024-07-252024-07-252024Lee, S., Bondaruk, J., Wang, Y., Chen, H., Lee, J. G., Majewski, T., Mullen, R. D., Cogdell, D., Chen, J., Wang, Z., Yao, H., Kus, P., Jeong, J., Lee, I., Choi, W., Navai, N., Guo, C., Dinney, C., Baggerly, K., … Czerniak, B. (2024). Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis. Cell Reports, 43(5). https://doi.org/10.1016/j.celrep.2024.114146https://hdl.handle.net/1911/117498We 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.engExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Journal articlePIIS2211124724004741https://doi.org/10.1016/j.celrep.2024.114146