Browsing by Author "Lee, Sangkyou"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    The origin of bladder cancer from mucosal field effects
    (Cell Press, 2022) Bondaruk, Jolanta; Jaksik, Roman; Wang, Ziqiao; Cogdell, David; Lee, Sangkyou; Chen, Yujie; Dinh, Khanh Ngoc; Majewski, Tadeusz; Zhang, Li; Cao, Shaolong; Tian, Feng; Yao, Hui; Kuś, Paweł; Chen, Huiqin; Weinstein, John N.; Navai, Neema; Dinney, Colin; Gao, Jianjun; Theodorescu, Dan; Logothetis, Christopher; Guo, Charles C.; Wang, Wenyi; McConkey, David; Wei, Peng; Kimmel, Marek; Czerniak, Bogdan
    Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multiple HOX genes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of mucosa. The α mutations occurred at low frequencies while the β mutations increased in frequency with disease progression. Modeling revealed that bladder carcinogenesis spans 10–15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was driven by β mutations.
  • Thumbnail Image
    Item
    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.