KRAS mutation and epithelial-macrophage interplay in pancreatic neoplastic transformation

Int J Cancer. 2018 Oct 15;143(8):1994-2007. doi: 10.1002/ijc.31592. Epub 2018 Aug 9.


Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased (i) ductal to acinar gene expression ratios, (ii) epithelial cells proliferation and (iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a protumorigenic phenotype in macrophages. Altered macrophages decreased epithelial pigment epithelial derived factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) and in our human PDA specimens. Epithelium-macrophage cross-talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a protumorigenic phenotype in macrophages, in turn augmenting neoplastic growth.

Keywords: KRAS; PEDF; macrophage; pancreas cancer.

Publication types

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

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Female
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation / genetics*
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • RAW 264.7 Cells


  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)

Supplementary concepts

  • Pancreatic Carcinoma