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.
-
Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammationNCBI Gene Expression Omnibus, GSE140484.
-
TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal AdenocarcinomaNCBI Gene Expression Omnibus, GSE115463.
-
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).
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.
Metrics
-
- 7,144
- views
-
- 1,004
- downloads
-
- 71
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Citations by DOI
-
- 71
- citations for umbrella DOI https://doi.org/10.7554/eLife.53381
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
eLife 9:e53381.
https://doi.org/10.7554/eLife.53381
