Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
- Cold Spring Harbor Laboratory, United States
- University of Nebraska, United States
- University of Nebraska Medical Center, United States
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.
Data availability
The RNA-seq and ChIP-seq data in this study is available in the Gene Expression Omnibus database https://www.ncbi.nlm.nih.gov/geo/ with accession number GSE140484.
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Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammationNCBI Gene Expression Omnibus, GSE140484.
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TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal AdenocarcinomaNCBI Gene Expression Omnibus, GSE115463.
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Virtual Microdissection of Pancreatic Ductal Adenocarcinoma Reveals Tumor and Stroma SubtypesNCBI Gene Expression Omnibus, GSE71729.
Article and author information
Author details
Christopher R Vakoc
Funding
New York State Department of Health (C150158)
- Tim DD Somerville
National Cancer Institute (U10CA180944)
- David A Tuveson
National Cancer Institute (U01CA210240)
- David A Tuveson
National Cancer Institute (U01CA224013)
- David A Tuveson
National Cancer Institute (1R01CA188134)
- David A Tuveson
National Cancer Institute (1R01CA190092)
- David A Tuveson
Pershing Square Foundation
- Christopher R Vakoc
National Cancer Institute (5P01CA013106-Project 4)
- Christopher R Vakoc
National Cancer Institute (CA229699)
- Christopher R Vakoc
Pancreatic Cancer Action Network (16-20-25-VAKO)
- Christopher R Vakoc
Lustgarten Foundation
- David A Tuveson
National Cancer Institute (5P30CA45508)
- David A Tuveson
National Cancer Institute (5P50CA101955)
- David A Tuveson
National Cancer Institute (P20CA192996)
- David A Tuveson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures and studies were approved by the Cold Spring Harbor Laboratory Animal Care and Use Committee (IACUC protocol number 19-16-8).
Reviewing Editor
- Charles L Sawyers, Memorial Sloan Kettering Cancer Center, United States
Publication history
- Received: November 6, 2019
- Accepted: April 23, 2020
- Accepted Manuscript published: April 24, 2020 (version 1)
- Version of Record published: May 5, 2020 (version 2)
- Version of Record updated: May 12, 2020 (version 3)
Copyright
© 2020, Somerville et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
eLife 9:e53381.
https://doi.org/10.7554/eLife.53381
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