Abstract 1335: Involvement of canonical Wnt/β-catenin signaling pathway in pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, develops through the progression of premalignant lesions called pancreatic intraductal neoplasms (PanINs). Acinar-to-ductal metaplasia (ADM) is postulated to contribute to PanIN development, and the canonical Wnt/β-catenin pathway has been implicated in this process. To ascertain the impact of postnatal activation of the Wnt/β-catenin pathway in PanIN-PDAC progression, we combined the elasatse-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37A, but not RCAS-GFP, stimulated a shift to higher-grade PanIN lesions in young adult mice. Moreover, mice injected with RCAS-β-cateninS37A had reduced survival relative to RCAS-GFP controls (log-rank test; p <0.05). In addition, overexpression of active β-catenin or its DNA-binding partner TCF4 in PDAC cell lines enhanced cell proliferation, soft-agar colony formation, as well as migration and invasion activity. In contrast, these phenotypes were significantly blocked by the introduction of Icat, an inhibitor of the β-catenin/TCF4 interaction. Together, these data suggest that activation of the Wnt/β-catenin signaling pathway is closely related to pancreatic tumorigenesis and progression of this malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1335. doi:1538-7445.AM2012-1335