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Deletion of Lats 1 and 2 in mouse pancreatic acinar cells induces pancreatic fibrosis and inflammation

By Ming Gao, Jun Liu, Michael Nipper, Francis E Sharkey, Randy L Johnson, Howard C. Crawford, Yidong Chen, Pei Wang

Posted 23 Jan 2019
bioRxiv DOI: 10.1101/522938

Objective: The Hippo signaling pathway is known for regulating proliferation, differentiation, organ size, and tumorigenesis. Large tumor suppressor kinase 1 and 2 (LATS1&2) are the core kinases of this pathway, whose functions in the normal pancreas and pancreatic diseases are unclear. We studied the function of LATS1&2 specifically in pancreatic acinar cells of adult mice. Design: We generated mice with adult pancreatic acinar cell-specific deletion of Lats1&2 genes by using CreER/LoxP. Pancreata were analyzed by histological examination, immunostaining, western blot, and RNA-sequencing. Results: Deletion of Lats1&2 genes in adult pancreatic acinar cells resulted in rapid development of pancreatic inflammation and fibrosis. Loss of Lats1&2 did not directly induce acinar cell proliferation or apoptosis, but resulted in pancreatic stellate cell (PSC) activation followed by immune cell infiltration and acinar-to-ductal metaplasia. These effects were mediated by the Hippo downstream effectors YAP1/TAZ. By using neutralizing antibody to block CTGF, one of their targets, the inflammation and fibrosis were reduced. Our RNA-sequencing data identified upregulation of fibroinflammatory genes in Lats1&2 null pancreata, which may play important roles in stimulating PSC activation and promoting pancreatic fibrosis, as well as inflammation. Conclusions: Deletion of the Lats1&2 genes from adult acinar cells leads to the YAP1/TAZ dependent upregulation of a fibroinflammatory program. Our results emphasize the critical role of the Lats1&2 in regulating PSC activation. Our findings identify new strategies for controlling pancreatic inflammation and fibrosis in diseases such as pancreatitis and pancreatic cancer. Key words: Hippo; pancreatic stellate cells; YAP1/TAZ; pancreatitis

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