Abstract 4087: Investigating the novel role of Hippo signaling in mouse pancreas

Abstract

Listen

Translate article

Abstract Background: Large tumor suppressor kinase 1 and 2 are the core kinases of the Hippo signaling pathway, and play critical roles in regulating cell growth and organ size during animal development. Inactivation of the Hippo signaling pathway has been demonstrated to initiate tumor development in certain organs. However, the function of Lats1&2 in the pancreas is still elusive. Methods and results: To investigate the function of Lats1&2 in the pancreas, we generated mice with adult pancreatic acinar cell-specific deletion of Lats1&2 genes. Interestingly, instead of enlarging of the pancreas or pancreatic tumorigenesis, the deletion of Lats1&2 genes in pancreatic acinar cells resulted in severe inflammation of the pancreas. To further examine the mechanisms, we took advantage of a Rosa26 reporter to trace individual Lats1&2 null cells in vivo. We found that the loss of Lats1&2 did not affect cell growth directly but activated pancreatic stellate cells. This was followed by immune cell infiltration and acinar-to-ductal metaplasia in Lats1&2 null pancreas. Our RNA seq data revealed several cytokines and chemokine genes, such as ctgf, spp1, cxcl12, cxcl16, were gradually unregulated with time in Lats1&2 null pancreas before immune cell infiltration. Finally, we revealed the phenotype of Lats1&2 DKO mouse was in a YAP1/TAZ-dependent manner. Conclusion and significance: In our present study, our data suggested that deletion of the Lats1&2 genes in acinar cells caused pancreatitis through activation of pancreatic stellate cells directly. Our study discovered a new mechanism of the inflammatory response initiated by pancreatic epithelial cells and regulated by the Hippo signaling pathway, which is likely to be useful for the identification of new strategies for controlling pancreatic inflammation and prevention of pancreatic cancer. Citation Format: Ming Gao, Jun Liu, Francis E. Sharkey, Howard C. Crawford, Randy L. Johnson, Yidong Chen, Pei Wang. Investigating the novel role of Hippo signaling in mouse pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4087.