Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Elife. 2020 Apr 24;9:e53381. doi: 10.7554/eLife.53381.

Abstract

A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

Keywords: TP63; cancer biology; cancer-associated fibroblasts; human; human biology; inflammation; medicine; mouse; pancreatic cancer; squamous; trans-differentiation.

Publication types

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

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / physiology
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Lineage
  • Cell Transdifferentiation / physiology*
  • Cytokines / genetics
  • Cytokines / physiology
  • Humans
  • Inflammation / pathology*
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophil Infiltration
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology*
  • Stromal Cells / pathology
  • Tumor Microenvironment

Substances

  • CKAP4 protein, human
  • Cytokines
  • Membrane Proteins

Associated data

  • GEO/GSE140484
  • GEO/GSE115463
  • GEO/GSE71729