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Emerging evidence suggests that metformin, an activator of AMP-activated protein kinase (AMPK), may be useful in preventing and treating pancreatic ductal adenocarcinoma (PDAC). However, whether metformin has an effect on the stromal reaction of PDAC remains unknown. In this study, we first evaluated the expression of AMPK and phosphorylated-AMPK (P-AMPK) in normal and PDAC tissues, our data indicate that reduced P-AMPK expression is a frequent event in PDAC and correlated with poor prognosis and the dense stromal reaction. We then determined the efficacy of metformin on PDAC growth in vitro and in vivo. We reveal that metformin reduces the production of fibrogenic cytokines from pancreatic cancer cells (PCs) and inhibits paracrine-mediated pancreatic stellate cells (PSCs) activation under PCssingle bondPSCs co-culture conditions. By using a xenograft PDAC mouse model, we show that …