Molecular and Cellular Pathobiology Oncogenic HRAS Activates Epithelial-to- Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas

Muscle-invasive urothelial carcinomas of the bladder (MIUCB) exhibit frequent receptor tyrosine kinase alterations, but the precise nature of their contributions to tumor pathophysiology is unclear. Using mutant HRAS (HRAS ) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year. This persistent hyperplastic state appeared to result from an equilibrium between promitogenic factors and compensatory tumor barriers in the p19–MDM2–p53–p21 axis and a prolonged G2 arrest. Conditional inactivation of p53 in urothelial cells of transgenic mice expressing HRAS resulted in carcinoma in situ and basal-subtype MIUCB with focal squamous differentiation resembling the human counterpart. The transcriptome of microdissected MIUCB was enriched in genes that drive epithelial-to-mesenchymal transition, the upregulation ofwhich is associatedwith urothelial cells expressingmultiple progenitor/stem cellmarkers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker thatmay inform the progression and treatment of urothelial carcinoma. Cancer Res; 75(10); 2017–28. 2015 AACR.