Abstract 1442: Establishing a papillary renal cell carcinoma mouse model with activating Met mutation

Abstract Renal cell carcinoma (RCC) is a heterogeneous group of cancers of the nephron. Papillary renal cell carcinoma (PRCC) is the second most common type of RCC. c-Met activating mutations have been associated with Type 1 PRCC which are made up of small cells containing basophilic cytoplasm covering papillae and tubular structures. In patients with PRCC, c-MetH1112Y missense mutations are associated with both somatic and germline mutations. Previous functional studies indicate codon H1112 plays an important structural role in maintaining c-Met in the inactive conformation and alterations at this codon, including H1112Y, likely disrupt this interaction facilitating constitutive activation with increased c-MET activity. A c-MetH1112Y (c-MetHY) transgene with tetO promoter sequence was micro-injected into the mouse oocyte. Transgenic mice carrying this transgene have the ability to express this activated Met protein in cells expressing rtTA (reverse tetracycline-controlled transactivator) and when doxycycline is present. Mutant mice harboring this transgene along with additional trp53 mutations showed glomeruloid like Type 1 PRCC. Our in vivo studies confirmed the expression of c-MetHY gene within the kidney and Lrp2 and Ki67 staining indicated that PRCC arises from PT (proximal tubule). PRCC canonical markers CK7, AMACR and MET expression confirmed the Type1 PRCC in our mouse model. Additionally Pan-CK, E-Cad positive expression in mutant mice further confirmed PRCC arises from epithelial cells. We have generated and described type 1 PRCC mouse model with activating-MetHY mutation. This mouse model will help illustrate the oncogenic mechanism of Met activation and identify the critical events during progression of PRCC. Citation Format: Preet Lal, Li Ding, Feng Chen. Establishing a papillary renal cell carcinoma mouse model with activating Met mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1442.