Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis

Science. 2021 Sep 17;373(6561):eabj0486. doi: 10.1126/science.abj0486. Epub 2021 Sep 17.


Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / pathology*
  • Animals
  • Carcinogenesis*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology*
  • Carcinoma, Pancreatic Ductal / physiopathology
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Cellular Reprogramming
  • Chromatin / metabolism
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Enzyme Precursors / metabolism
  • Epigenesis, Genetic
  • Epithelial Cells / pathology
  • Epithelial Cells / physiology
  • Female
  • Genes, ras*
  • MAP Kinase Signaling System
  • Male
  • Metaplasia
  • Mice
  • Mutation
  • Pancreas / metabolism
  • Pancreas / pathology*
  • Pancreatitis / genetics
  • Pancreatitis / immunology
  • Pancreatitis / physiopathology*
  • Spheroids, Cellular
  • Transcriptome


  • Chromatin
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Enzyme Precursors