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

Abstract

ObjectiveThe 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 both the normal pancreas and pancreatic diseases are unclear. We studied the function of LATS1&2 specifically in pancreatic acinar cells of adult mice. DesignWe 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. ResultsDeletion 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, a YAP1/TAZ target, 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. ConclusionsDeletion 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 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.