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Original article
Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy
  1. Bo Kong1,2,
  2. Philipp Bruns1,3,
  3. Nora A Behler1,
  4. Ligong Chang1,
  5. Anna Melissa Schlitter4,
  6. Jing Cao1,
  7. Andreas Gewies5,6,7,
  8. Jürgen Ruland5,7,8,
  9. Sina Fritzsche1,
  10. Nataliya Valkovskaya1,
  11. Ziying Jian1,
  12. Ivonne Regel9,
  13. Susanne Raulefs1,
  14. Martin Irmler10,
  15. Johannes Beckers10,11,12,
  16. Helmut Friess1,
  17. Mert Erkan13,
  18. Nikola S Mueller3,
  19. Susanne Roth14,
  20. Thilo Hackert14,
  21. Irene Esposito9,
  22. Fabian J Theis3,15,
  23. Jörg Kleeff1,16,
  24. Christoph W Michalski14
  1. 1Department of Surgery, Technische Universität München (TUM), Munich, Germany
  2. 2Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
  3. 3Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany
  4. 4Institute of Pathology, TUM, Munich, Germany
  5. 5Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany
  6. 6Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany
  7. 7German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
  8. 8German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
  9. 9Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany
  10. 10Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
  11. 11Chair of Experimental Genetics, Technische Universität München, Freising, Germany
  12. 12Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany
  13. 13Department of Surgery, Koc University, Istanbul, Turkey
  14. 14Department of Surgery, University of Heidelberg, Heidelberg, Germany
  15. 15Department of Mathematics, TUM, Munich, Germany
  16. 16NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
  1. Correspondence to Dr Christoph W Michalski, Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany; cwmichalski{at}gmail.com

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.

  • PANCREATIC CANCER
  • SIGNAL TRANSDUCTION

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