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

Objective: The Hippo signaling pathway is known for regulating proliferation, differentiation, organ size, and tumorigenesis. Large tumor suppressor kinase 1 and 2 (LATS1u00262) are the core kinases of this pathway, whose functions in the normal pancreas and pancreatic diseases are unclear. We studied the function of LATS1u00262 specifically in pancreatic acinar cells of adult mice. Design: We generated mice with adult pancreatic acinar cell-specific deletion of Lats1u00262 genes by using CreER/LoxP. Pancreata were analyzed by histological examination, immunostaining, western blot, and RNA-sequencing. Results: Deletion of Lats1u00262 genes in adult pancreatic acinar cells resulted in rapid development of pancreatic inflammation and fibrosis. Loss of Lats1u00262 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 Lats1u00262 null pancreata, which may play important roles in stimulating PSC activation and promoting pancreatic fibrosis, as well as inflammation. Conclusions: Deletion of the Lats1u00262 genes from adult acinar cells leads to the YAP1/TAZ dependent upregulation of a fibroinflammatory program. Our results emphasize the critical role of the Lats1u00262 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