Browsing by Author "Choi, Woonyoung"

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    Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis
    (Elsevier, 2024) 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
    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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    Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer
    (Cell Press, 2020) Yang, Guoliang; Bondaruk, Jolanta; Cogdell, David; Wang, Ziqiao; Lee, Sangkyou; Lee, June Goo; Zhang, Shizhen; Choi, Woonyoung; Wang, Yan; Liang, Yu; Wang, Gang; Wang, Ying; Yao, Hui; Dadhania, Vipulkumar; Gao, Jianjun; Logothetis, Christopher; Siefker-Radtke, Arlene; Kamat, Ashish; Dinney, Colin; Theodorescu, Dan; Kimmel, Marek; Wei, Peng; Guo, Charles C.; Weinstein, John N.; McConkey, David J.; Czerniak, Bogdan
    We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with The Cancer Genome Atlas cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation signature 3 associated with loss of BRCA1/2 function. SCCs were characterized by downregulation of luminal and basal markers and were referred to as double-negative. Transcriptome analyses indicated that SCCs displayed lineage plasticity driven by a urothelial-to-neural phenotypic switch with a dysregulated epithelial-to-mesenchymal transition network. SCCs were depleted of immune cells, and expressed high levels of the immune checkpoint receptor, adenosine receptor A2A (ADORA2A), which is a potent inhibitor of immune infiltration. Our observations have important implications for the prognostication and development of more effective therapies for this lethal bladder cancer variant.