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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-05, Vol.75 (10), p.2017-2028
• Main Authors: He, Feng, Melamed, Jonathan, Tang, Moon-Shong, Huang, Chuanshu, Wu, Xue-Ru
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - pathology; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Matrix Metalloproteinases, Secreted - metabolism; Mice, Knockout; Muscle, Smooth - pathology; Neoplasm Invasiveness; Neoplastic Stem Cells - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - physiology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urothelium
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-3067

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 of which is associated with urothelial cells expressing multiple progenitor/stem cell markers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker that may inform the progression and treatment of urothelial carcinoma.