Abstract 5154: Modeling luminal urothelial carcinoma in the bladder and the upper tract

Abstract Introduction: Pan-urothelial carcinoma (panUCC) involves synchronous or metachronous urothelial carcinoma of the bladder (UCB) and upper tract urothelial carcinoma (UTUC). We sought to model panUCC using a triple knockout (TKO: Trp53; Rb1; Pten) genetically engineered mouse model (GEMM). Methods: Using a urothelium-specific Uroplakin 2-Cre ERT2 (Upk2-CreERT2), we generated novel TKO mice (Upk2-Cre ERT2; Trp53f/f; Rb1f/f; Ptenf/f). The mice were monitored for hematuria, urine retention, tumor formation, and survival. PCR primers were designed to amplify the genes after recombination. Tumor histology and metastasis were examined by hematoxylin and eosin (HE) and immunohistochemistry (IHC). The subtype of tumors was classified using luminal (Upk3, CK8, GATA-3) and basal markers (CK5, p63), and a neuroendocrine marker (synaptophysin, Syp). Results: Upk2-CreERT2; TKO mice (n = 34, 18 males and 16 females) developed non-muscle invasive urothelial carcinoma tumors located in the bladder and/or the renal pelvis/ureter with a median survival of 294 days. PCR results validated Trp53/Rb1/Pten mutations in UC tumors. Mice with UCB or mixed UCB/UTUC tumors exhibited a longer survival compared to mice with UTUC only [median survival 393 days (n = 7) VS 278 days (n = 27), P = 0.006]. No obvious evidence of distant metastases was detected. IHC of both UCB and UTUC tumors demonstrated luminal UC tumors with strong expression of luminal markers (Upk3, CK8, GATA-3) and no expression of basal and neuroendocrine markers (CK5, p63, and Syp). Conclusion: We developed a novel TKO GEMM that faithfully recapitulates human panUCC. This GEMM provides a useful tool for investigating the molecular and therapeutic differences between UCB and UTUC tumors. Funding: This research work was supported in part by NIH Grants, K08CA252161(Li, Q), P30CA016056 (NCI Cancer Center Core Support Grant), and the Roswell Park Alliance Foundation. Citation Format: Dongbo Xu, Kyle Wieczorek, Li Wang, Yali Zhang, Jianmin Wang, Bo Xu, David W. Goodrich, Ahmed A. Hussein, Khurshid Guru, Qiang Li. Modeling luminal urothelial carcinoma in the bladder and the upper tract [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5154.