Abstract A08: Activation of Wnt/β-catenin in acinar cells accelerates Kras-induced PDAC, while activation of Wnt signaling pathways in stroma induces mucinous cystic neoplasm

Pancreatic ductal adenocarcinoma (PDAC) commonly develops following activating mutations in the KRAS oncogene. Activation of the Wnt signaling pathway is also commonly observed in PDAC, yet whether Wnt ligand induced signaling promotes pancreatic tumorigenesis in vivo remains unclear. 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-Kras G12D , Ptf1a-cre model. Delivery of RCAS viruses encoding β-catenin S37A and Wnt1 stimulated the progression of premalignant PanIN and PDAC development. Mice injected with RCAS-β-catenin S37A and Wnt1 had reduced survival relative to RCAS-GFP controls (log-rank test; p S37A nor RCAS-GFP, developed mucinous cystic neoplasm (MCN). These lesions displayed stereotypical ovarian-like stroma that was positive for estrogen receptor (ER) and progesterone receptor (PR), but they lacked the typical mucinous epithelium observed in human MCN. Analysis of tissue specimens confirmed of activation of both the Wnt/β-catenin and PCP signaling pathways in the stroma, but not the epithelium of MCN lesions. Analysis of human MCN cases identified activation of these Wnt signaling pathways in the ovarian-like stroma, but not the cyst epithelium. Together, these data suggest that the Wnt/β-catenin signaling pathway in acinar cells stimulates Kras-induced PDAC development, while activation of Wnt signaling pathways in the stroma stimulates the development of the ovarian-like stroma and contributes to MCN formation in vivo. Citation Format: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, David S. Klimstra, Brian C. Lewis. Activation of Wnt/β-catenin in acinar cells accelerates Kras-induced PDAC, while activation of Wnt signaling pathways in stroma induces mucinous cystic neoplasm. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A08.