Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

• DOI: 10.7554/elife.53381
• Publication Date: 2020-04-24T12:00:15Z
• Authors: Tim DD Somerville; Giulia Biffi; Juliane Daßler-Pl...; Stella K Hur; Xue-Yan He; Krysten E Vance; Koji Miyabayashi; Yali Xu; Diogo Maia-Silva; Olaf Klingbeil; Osama E Demerdash; Jonathan B Preall; Michael A Holling...; Mikala Egeblad; David A Tuveson; Christopher R Vakoc
• Keywords: CXCL1

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