Bo Kong1,2, Philipp Bruns1,3, Nora A Behler1, Ligong Chang1, Anna Melissa Schlitter4, Jing Cao1, Andreas Gewies5,6,7, Jürgen Ruland5,7,8, Sina Fritzsche1, Nataliya Valkovskaya1, Ziying Jian1, Ivonne Regel9, Susanne Raulefs1, Martin Irmler10, Johannes Beckers10,11,12, Helmut Friess1, Mert Erkan13, Nikola S Mueller3, Susanne Roth14, Thilo Hackert14, Irene Esposito9, Fabian J Theis3,15, Jörg Kleeff1,16, Christoph W Michalski14. 1. Department of Surgery, Technische Universität München (TUM), Munich, Germany. 2. Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. 3. Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany. 4. Institute of Pathology, TUM, Munich, Germany. 5. Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany. 6. Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany. 7. German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany. 8. German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. 9. Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. 10. Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany. 11. Chair of Experimental Genetics, Technische Universität München, Freising, Germany. 12. Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany. 13. Department of Surgery, Koc University, Istanbul, Turkey. 14. Department of Surgery, University of Heidelberg, Heidelberg, Germany. 15. Department of Mathematics, TUM, Munich, Germany. 16. NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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 mousepancreas 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Kristy Boggs; Ting Wang; Abrahim I Orabi; Amitava Mukherjee; John F Eisses; Tao Sun; Li Wen; Tanveer A Javed; Farzad Esni; Wei Chen; Sohail Z Husain Journal: Sci Rep Date: 2018-01-23 Impact factor: 4.379
Authors: L Dumartin; W Alrawashdeh; S M Trabulo; T P Radon; K Steiger; R M Feakins; M P di Magliano; C Heeschen; I Esposito; N R Lemoine; T Crnogorac-Jurcevic Journal: Oncogene Date: 2016-12-12 Impact factor: 9.867