Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy

Gut. 2018 Jan;67(1):146-156. doi: 10.1136/gutjnl-2015-310913. Epub 2016 Sep 19.

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.

Keywords: PANCREATIC CANCER; SIGNAL TRANSDUCTION.

MeSH terms

  • Acinar Cells / pathology
  • Acute Disease
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Proliferation / genetics
  • Disease Models, Animal
  • Disease Progression
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Mesenchymal Stem Cells / pathology
  • Mice, Transgenic
  • Pancreas / physiology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Pancreatitis / genetics
  • Pancreatitis / pathology
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Regeneration / genetics

Substances

  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)