Publication Date
5-28-2024
Journal
Cell Reports
Abstract
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.
Keywords
Aged, Aged, 80 and over, Animals, Female, Humans, Male, Mice, Middle Aged, Carcinogenesis, Cell Differentiation, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Receptors, Lysophosphatidic Acid, Urinary Bladder Neoplasms, Urothelium
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Internal Medicine Commons, Male Urogenital Diseases Commons, Medical Sciences Commons, Oncology Commons, Urology Commons
Comments
Supplementary Materials
PMID: 38676926