title: Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas.
abstract: 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.
authors: Department of Urology, New York University School of Medicine, New York, New York. Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, New York.
authors: Feng
authors: F
authors: He
authors: Department of Pathology, New York University School of Medicine, New York, New York.
authors: Jonathan
authors: J
authors: Melamed
authors: Department of Environmental Medicine, New York University School of Medicine, New York, New York.
authors: Moon-Shong
authors: MS
authors: Tang
authors: Department of Environmental Medicine, New York University School of Medicine, New York, New York.
authors: Chuanshu
authors: C
authors: Huang
authors: Department of Urology, New York University School of Medicine, New York, New York. Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York. xue-ru.wu@med.nyu.edu.
authors: Xue-Ru
authors: XR
authors: Wu
mesh_terms: D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000473:pathology; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology*; D019459:Urothelium
chemical_list: D016159:Tumor Suppressor Protein p53; D053505:Matrix Metalloproteinases, Secreted; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)