RT Journal Article SR Electronic T1 Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 146 OP 156 DO 10.1136/gutjnl-2015-310913 VO 67 IS 1 A1 Bo Kong A1 Philipp Bruns A1 Nora A Behler A1 Ligong Chang A1 Anna Melissa Schlitter A1 Jing Cao A1 Andreas Gewies A1 Jürgen Ruland A1 Sina Fritzsche A1 Nataliya Valkovskaya A1 Ziying Jian A1 Ivonne Regel A1 Susanne Raulefs A1 Martin Irmler A1 Johannes Beckers A1 Helmut Friess A1 Mert Erkan A1 Nikola S Mueller A1 Susanne Roth A1 Thilo Hackert A1 Irene Esposito A1 Fabian J Theis A1 Jörg Kleeff A1 Christoph W Michalski YR 2018 UL http://gut.bmj.com/content/67/1/146.abstract AB Objective The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined.Design We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated KrasG12D-driven pancreatic ductal adenocarcinoma. Quantitative expression data were analysed and extensively modelled in silico.Results We defined three distinctive phases—termed inflammation, regeneration and refinement—following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer.Conclusions These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.