Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Tim DD Somerville

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  2. Giulia Biffi

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  3. Juliane Daßler-Plenker

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  4. Stella K Hur

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  5. Xue-Yan He

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  6. Krysten E Vance

    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Omaha, United States
    Competing interests
    No competing interests declared.
  7. Koji Miyabayashi

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  8. Yali Xu

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  9. Diogo Maia-Silva

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  10. Olaf Klingbeil

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  11. Osama E Demerdash

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  12. Jonathan B Preall

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  13. Michael A Hollingsworth

    Eppley Institute, University of Nebraska Medical Center, Omaha, United States
    Competing interests
    No competing interests declared.
  14. Mikala Egeblad

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  15. David A Tuveson

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    David A Tuveson, an advisor to Surface, Leap, and Cygnal and has stock ownership in Surface and Leap.
  16. Christopher R Vakoc

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    vakoc@cshl.edu
    Competing interests
    Christopher R Vakoc, has received funding from Boehringer-Ingelheim and is an advisor to KSQ Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1158-7180

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

  1. 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

  1. Received: November 6, 2019
  2. Accepted: April 23, 2020
  3. Accepted Manuscript published: April 24, 2020 (version 1)
  4. Version of Record published: May 5, 2020 (version 2)
  5. 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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  1. Tim DD Somerville
  2. Giulia Biffi
  3. Juliane Daßler-Plenker
  4. Stella K Hur
  5. Xue-Yan He
  6. Krysten E Vance
  7. Koji Miyabayashi
  8. Yali Xu
  9. Diogo Maia-Silva
  10. Olaf Klingbeil
  11. Osama E Demerdash
  12. Jonathan B Preall
  13. Michael A Hollingsworth
  14. Mikala Egeblad
  15. David A Tuveson
  16. Christopher R Vakoc
(2020)
Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
eLife 9:e53381.
https://doi.org/10.7554/eLife.53381

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https://doi.org/10.7554/eLife.53381

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