Abstract B25: Activation of Wnt/β-catenin signaling pathway enhances pancreatic cancer development and the malignant potential via up-regulation of Cyr61/CCN1

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 pathway 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. Indeed, mice injected with RCAS-β-cateninS37A and Wnt1 had reduced survival relative to RCAS-GFP controls (P < 0.05). 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. Meanwhile, we identified Cyr61/CCN1 as a target molecule for Wnt/β-catenin signaling pathway in PDAC. Nuclear β-catenin and Cyr61/CCN1 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin and Cyr61/CCN1-positivity independently correlated with poor prognosis (P < 0.01). Knockdown of Cyr61/CCN1 in a β-catenin-activated PDAC 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/CCN1. Citation Format: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, Brian Quattrochi, Victoria A. Appleman, Jianhong Ou, Lihua Julie Zhu, Nao Yoshida, Shintaro Yamazaki, Tadatoshi Takayama, Masahiko Sugitani, Norimichi Nemoto, David S. Klimstra, Brian C. Lewis.{Authors}. Activation of Wnt/β-catenin signaling pathway enhances pancreatic cancer development and the malignant potential via up-regulation of Cyr61/CCN1. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B25.