IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30392-7.html
   My bibliography  Save this article

Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ

Author

Listed:
  • Yi Liu

    (The University of Texas MD Anderson Cancer Center)

  • Yasunori Deguchi

    (The University of Texas MD Anderson Cancer Center)

  • Daoyan Wei

    (The University of Texas MD Anderson Cancer Center)

  • Fuyao Liu

    (The University of Texas MD Anderson Cancer Center)

  • Micheline J. Moussalli

    (The University of Texas MD Anderson Cancer Center
    University of Michigan)

  • Eriko Deguchi

    (The University of Texas MD Anderson Cancer Center)

  • Donghui Li

    (The University of Texas MD Anderson Cancer Center)

  • Huamin Wang

    (The University of Texas MD Anderson Cancer Center)

  • Lovie Ann Valentin

    (The University of Texas MD Anderson Cancer Center)

  • Jennifer K. Colby

    (The University of Texas MD Anderson Cancer Center)

  • Jing Wang

    (The University of Texas MD Anderson Cancer Center)

  • Xiaofeng Zheng

    (The University of Texas MD Anderson Cancer Center)

  • Haoqiang Ying

    (The University of Texas MD Anderson Cancer Center)

  • Mihai Gagea

    (The University of Texas MD Anderson Cancer Center)

  • Baoan Ji

    (Mayo Clinic)

  • Jiaqi Shi

    (University of Michigan)

  • James C. Yao

    (The University of Texas MD Anderson Cancer Center)

  • Xiangsheng Zuo

    (The University of Texas MD Anderson Cancer Center)

  • Imad Shureiqi

    (The University of Texas MD Anderson Cancer Center
    University of Michigan)

Abstract

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This PPARδ activation induces KRASmu pancreatic epithelial cells to secrete CCL2, which recruits immunosuppressive macrophages and myeloid-derived suppressor cells into pancreas via the CCL2/CCR2 axis to orchestrate an immunosuppressive tumor microenvironment and subsequently drive PanIN progression to PDAC. Our data identify PPARδ signaling as a potential molecular target to prevent PDAC development in subjects harboring PanINs.

Suggested Citation

  • Yi Liu & Yasunori Deguchi & Daoyan Wei & Fuyao Liu & Micheline J. Moussalli & Eriko Deguchi & Donghui Li & Huamin Wang & Lovie Ann Valentin & Jennifer K. Colby & Jing Wang & Xiaofeng Zheng & Haoqiang , 2022. "Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30392-7
    DOI: 10.1038/s41467-022-30392-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30392-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-30392-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30392-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.