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.
Reviewing Editor
- Charles L Sawyers, Memorial Sloan Kettering Cancer Center, United States
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).
Version 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.
Metrics
-
- 6,542
- views
-
- 937
- downloads
-
- 60
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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
Further reading
-
- Cancer Biology
- Cell Biology
Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.
-
- Cancer Biology
- Cell Biology
Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by the CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and cervical tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.
