title: Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.|Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.|Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Bruns
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Behler
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Ligong
authors.initials: L
authors.lastname: Chang
authors.affiliation: Institute of Pathology, TUM, Munich, Germany.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Cao
authors.affiliation: Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany.|Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany.|German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gewies
authors.affiliation: Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany.|German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Fritzsche
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Valkovskaya
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Raulefs
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany.|Chair of Experimental Genetics, Technische Universität München, Freising, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Koc University, Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany.
authors.forename: Nikola S
authors.initials: NS
authors.lastname: Mueller
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roth
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.affiliation: Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany.|Department of Mathematics, TUM, Munich, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.|NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
mesh_terms: D061354:Acinar Cells / Q000473:pathology; D000208:Acute Disease; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology; D008822:Mice, Transgenic; D010179:Pancreas / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012038:Regeneration / Q000235:genetics
chemical_list: C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: PANCREATIC CANCER; SIGNAL TRANSDUCTION