IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-06001-x.html
   My bibliography  Save this article

Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells

Author

Listed:
  • Stephanie Jaeckel

    (Ludwig-Maximilians-Universität München)

  • Markus Kaller

    (Ludwig-Maximilians-Universität München)

  • Rene Jackstadt

    (Ludwig-Maximilians-Universität München)

  • Ursula Götz

    (Ludwig-Maximilians-Universität München)

  • Susanna Müller

    (Ludwig-Maximilians-Universität München)

  • Sophie Boos

    (Ludwig-Maximilians-Universität München
    German Cancer Consortium (DKTK), Partner site Munich
    German Cancer Research Center (DKFZ))

  • David Horst

    (Ludwig-Maximilians-Universität München
    German Cancer Consortium (DKTK), Partner site Munich
    German Cancer Research Center (DKFZ)
    Charité – Universitätsmedizin Berlin)

  • Peter Jung

    (Ludwig-Maximilians-Universität München
    German Cancer Consortium (DKTK), Partner site Munich
    German Cancer Research Center (DKFZ))

  • Heiko Hermeking

    (Ludwig-Maximilians-Universität München
    German Cancer Consortium (DKTK), Partner site Munich
    German Cancer Research Center (DKFZ))

Abstract

The gene encoding the transcription factor TFAP4/AP4 represents a direct target of the c-MYC oncoprotein. Here, we deleted Ap4 in ApcMin mice, a preclinical model of inherited colorectal cancer. Ap4 deficiency extends their average survival by 110 days and decreases the formation of intestinal adenomas and tumor-derived organoids. The effects of Ap4 deletion are presumably due to the reduced number of functional intestinal stem cells (ISCs) amenable to adenoma-initiating mutational events. Deletion of Ap4 also decreases the number of colonic stem cells and increases the number of Paneth cells. Expression profiling revealed that ISC signatures, as well as the Wnt/β-catenin and Notch signaling pathways are downregulated in Ap4-deficient adenomas and intestinal organoids. AP4-associated signatures are conserved between murine adenomas and human colorectal cancer samples. Our results establish Ap4 as rate-limiting mediator of adenoma initiation, as well as regulator of intestinal and colonic stem cell and Paneth cell homeostasis.

Suggested Citation

  • Stephanie Jaeckel & Markus Kaller & Rene Jackstadt & Ursula Götz & Susanna Müller & Sophie Boos & David Horst & Peter Jung & Heiko Hermeking, 2018. "Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06001-x
    DOI: 10.1038/s41467-018-06001-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-06001-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-06001-x?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:9:y:2018:i:1:d:10.1038_s41467-018-06001-x. 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.