Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated 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 pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-β-cateninS37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P < .05). Ectopic expression of active β-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the β-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/β-catenin signaling pathway in pancreatic cancer cells. Nuclear β-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P < .01). Knockdown of CYR61 in a β-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/β-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.

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 &lt; 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

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 &lt;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

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