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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URL: https://pubmed.ncbi.nlm.nih.gov/32329713/
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.

Item Type: Paper
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL labs > Preall lab
CSHL labs > Tuveson lab
CSHL labs > Vakoc lab
Watson School
Watson School > Publications
Depositing User: Adrian Gomez
Date: 24 April 2020
Date Deposited: 07 May 2020 14:10
Last Modified: 06 Jul 2020 15:06
PMCID: PMC7200154
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Dataset ID:
URI: https://repository.cshl.edu/id/eprint/39345

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