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.
Article and author information
Author details
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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