Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Somerville, T. D. D., Biffi, G., DaBler-Plenker, J., Hur, S.K., He, X.-Y., Vance, K.E., Miyabayashi, K., Xu, Y., Maia-Silva, D., Klingbeil, O., Demerdash, O. E., Preall, J. B., Hollingsworth, M. A., Egeblad, M., Tuveson, D. A., Vakoc, C. R. (April 2020) Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation. Elife, 9. e53381. ISSN 2050-084x (Public Dataset)

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal diseases & disorders > cancer > cancer-associated cell types diseases & disorders > cancer > cancer-associated cell types > cancer-associated fibroblast organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > inflammation > cytokines organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts diseases & disorders > inflammation organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent
CSHL Authors:	Vakoc, Christopher R. Tuveson, David A. Egeblad, Mikala Preall, Jonathan Somerville, Timothy Biffi, Giulia DaBler-Plenker, Juliane He, Xueyan Miyabayashi, Koji Xu, Yali Maia-Silva, Diogo Klingbeil, Olaf Hur, Stella K. Demerdash, Osama E.
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources > Animal Shared Resource CSHL labs > Egeblad lab CSHL labs > Preall lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab School of Biological Sciences > Publications
Depositing User:	Adrian Gomez
Date:	24 April 2020
Date Deposited:	07 May 2020 14:10
Last Modified:	01 Feb 2024 18:42
PMCID:	PMC7200154
Related URLs:	Publisher
Dataset ID:	GEO: GSE140484
URI:	https://repository.cshl.edu/id/eprint/39345

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