Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression

SummaryChronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.

► Stat3 mediates Kras-driven spontaneous and pancreatitis-induced PanIN formation
► Stat3 supports cell proliferation, aberrant inflammation, and upregulates MMP7
► MMP7 deletion limits tumor size and reduces metastasis in mice
► Serum MMP7 levels in human patients with PDA correlate with metastatic disease