Pancreatic STAT5 activation promotes KrasG12D- and inflammation- induced acinar-to-ductal metaplasia and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its predilection for late-stage presentation. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its functional role in KRAS-driven pancreatic tumorigenesis remains unclear. We found that high levels of STAT5 in tumor cells were associated with a poorer prognosis in patients. The loss of Stat5 in acinar cells significantly reduced the development of acinar-to-ductal metaplasia (ADM) and PDAC lesions driven by KRAS mutation and pancreatitis. IL-22 signaling, induced by chronic inflammation, enhanced KRAS-mutant mediated STAT5 phosphorylation and the tumor-promoting function of IL-22 depends on the activation of STAT5. Chromatin immunoprecipitation assays revealed that STAT5 was directly bound to the promoters of ADM mediators HNF4a. Acinar cells from KC and KCS mouse pancreata tissues infected with Ad5-Cre or Ad5 to induce KRAS mutation were obtained for RNA-seq to analyze the role of STAT5 in PDAC development.