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Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression Akihisa Fukuda, Sam C. Wang, John P. Morris, IV, Alexandra E. Folias, Angela Liou, Grace E. Kim, Shizuo Akira, Kenneth M. Boucher, Matthew A. Firpo, Sean J. Mulvihill, and Matthias Hebrok Cancer Cell 19, 441–455, April 12, 2011 Presenter : Peng-Ming Chen Commentator : Dr. Wu Chou Su Date/Time : 2011/09/22 16:10 -17:00 Location : Room 601,Med College Building Background : It has been shown that pancreatitis is a risk factor for pancreatic ductal adenocarcinoma (PDA) development because pancreatitis has been shown to promote the development of pancreatic intraepithelial neoplasia (PanIN) and PDA in Kras-driven mouse models of PDA. However, the molecular mechanisms involved in the PDA enhancing effect of pancreatitis are largely unknown. Stat3 is known to be involved in inflammation-associated tumorigenesis in many cancer types. Stat3 is aberrantly activated in human PDA and controls proliferation in PDA cell lines, but the role of Stat3 in Kras-dependent initiation of the PanIN/PDA lineage is unknown. MMP7 is overexpressed in PanIN and PDA, and associated with advanced tumor stage (tumor size, lymph node involvement, and distant metastasis), and poor clinical outcomes. Interestingly, MMP7 is induced through a Stat3-dependent mechanism in prostate and breast cancer cell lines. Objective: In this study, the investigators want to identify the role of STAT3 in the linkage of PanIN and PDA initiation and pancreatitis. Furthermore, the effect of STAT3-MMP7 signaling in pancreas is investigated, and they also want to know the role of MMP7 in PDA initiation and progression. Result: The investigators firstly examine the expression of activated Stat3 in the caerulin-induced acute pancreatitis in wild-type and KRASG12D mice model, which showed caerulin treatment would induce the expression of activated Stat3 in the pancreas and persistent Stat3 activation in Kras-driven ductal metaplatic cells. Mouse model with expressing KrasG12D and conditional Stat3 knockout (Ptf1a-Cre; KrasG12D; Stat3f/f) was established to study whether the presence of Stat3 would affect PanIN/PDA formation in caerulin-treated KRASG12D mice. Spontaneous and caerulin-induced PanIN formation was inhibited with pancreatic Stat3 deletion. Further study suggested that Stat3 is required to support persistent ductal cell proliferation of Kras-driven metaplastic ductal cells and PanIN of caerulin-treated KRASG12D mice. The expression level of inflammation-associated cytokine is also noted to be lower Kras-driven ductal metaplasia of Stat3 depleted mice. In addition, Stat3 supports MMP7 expression during Kras-driven PanIN development following caerulin-induced pancreatitis. Using MMP7 knockout mice, the investigator further demonstrated that MMP7 was not the direct effector of Stat3 for ductal metaplasia and PanIN development, but MMP7 signaling was important for tumor growth and metastasis. Clinically, the investigators found that the median survival of patients with metastatic PDA whose serum MMP7 level above and equal or below 20.2 ng/mL was 114.5 days and 329days, respectively. Conclusion: In this study, Fukuda et al. demonstrate that Stat3 contributes to pancreatic neoplasm Initiation, and MMP7 contributes to PDA progression and metastasis. Both Stat3 and MMP7 may be potentially novel targets to development future therapies for PDA. References : 1. Yamamoto, H., et al. (2001). Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J. Clin. Oncol. 19, 1118–1127. 2. Morris, J.P., et al. (2010). beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520.