Abstract 2742: Activation of Wnt/β-catenin signaling accelerates progression of Kras-induced pancreatic cancer.

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of the Wnt signaling pathway is also commonly observed in PDAC. To ascertain the impact of postnatal activation of the Wnt signaling pathways in PDAC development, we combined the elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37A and Wnt1 stimulated the progression of premalignant PanIN and PDAC development. Moreover, mice injected with RCAS-β-cateninS37A and Wnt1 had reduced survival relative to RCAS-GFP controls (log-rank test; p < 0.05). Meanwhile, active β-catenin or its DNA-binding partner TCF4 enhanced PDAC 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. Interestingly, Id2 (inhibitor of differentiation/DNA binding2) was significantly up-regulated by induction of β-catenin and TCF4, whereas Id2 expression was inhibited by Icat. Furthermore, nuclear β-catenin and Id2 were mainly observed in poorly differentiated PDACs and sarcomatoid tumors. Together, these data suggest that the Wnt/β-catenin signaling pathway stimulates pancreatic tumor development and progression through the activation of Id2. Citation Format: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, David S. Klimstra, Brian C. Lewis. Activation of Wnt/β-catenin signaling accelerates progression of Kras-induced pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2013-2742