The Role of Stat3 Signaling in the Initiation of Pancreatic Ductal Adenocarcinoma

Inflammation is a critical mediator of tumorigenesis. Chronic pancreatitis has been implicated as a risk factor for pancreatic ductal adenocarcinoma (PDA). A functional role for inflammation in PDA development is supported by recent findings that pancreatitis promotes neoplastic transformation of adult pancreatic acinar cells expressing oncogenic Kras, a hallmark mutation in the human disease. However, the underlying molecular mechanisms by which pancreatitis promotes the development of PDA remain unclear.  Signal transducer and activator of transcription 3 (Stat3) serves as a critical signaling node that integrates signals from cytokines and growth factors produced in part by infiltrating immune cells into transcriptional responses in target cells. Aberrant and persistent Stat3 activity is commonly found in many human malignancies and Stat3 activation in enterocytes has been recently linked to colitis-associated carcinogenesis. Furthermore, Stat3 is activated in human PDA, promotes proliferation in human PDA cell lines, and is also implicated in acinar-to-ductal metaplasia (ADM), which may be an early initiating step in ductal tumorigenesis. While these results suggest that Stat3 may play a role in PDA initiation and maintenance, the in vivo role of Stat3 in PDA pathogenesis has not been explored. Our preliminary data show that in the setting of constitutively activated Kras, aberrant Stat3 is persistently activated in response to injury during ADM and pancreatic intraepithelial neoplasia (PanIN) formation and that pancreatic epithelial Stat3 deletion results in decreased ADM formation. Therefore, , I hypothesize that pancreatic epithelial Stat3 activation links pancreatitis to PDA initiation. I propose to determine the in vivo role of Stat3 during PDA initiation and elucidate the mechanisms by which Stat3 mediates pancreatitis-induced PDA initiation using transgenic mouse models.It is anticipated that the research proposed here will provide novel insights into the mechanisms driving pancreatitis-induced PDA initiation and may suggest the development of novel therapeutic strategies.