IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-16309-2.html
   My bibliography  Save this article

An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development

Author

Listed:
  • Sunita Shankar

    (University of Michigan
    University of Michigan)

  • Jean Ching-Yi Tien

    (University of Michigan
    University of Michigan)

  • Ronald F. Siebenaler

    (University of Michigan
    University of Michigan)

  • Seema Chugh

    (University of Michigan
    University of Michigan)

  • Vijaya L. Dommeti

    (University of Michigan
    University of Michigan)

  • Sylvia Zelenka-Wang

    (University of Michigan
    University of Michigan)

  • Xiao-Ming Wang

    (University of Michigan
    University of Michigan)

  • Ingrid J. Apel

    (University of Michigan
    University of Michigan)

  • Jessica Waninger

    (University of Michigan
    University of Michigan)

  • Sanjana Eyunni

    (University of Michigan
    University of Michigan)

  • Alice Xu

    (University of Michigan
    University of Michigan)

  • Malay Mody

    (University of Michigan
    University of Michigan)

  • Andrew Goodrum

    (University of Michigan
    University of Michigan)

  • Yuping Zhang

    (University of Michigan
    University of Michigan)

  • John J. Tesmer

    (Purdue University)

  • Rahul Mannan

    (University of Michigan
    University of Michigan)

  • Xuhong Cao

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Pankaj Vats

    (University of Michigan
    University of Michigan)

  • Sethuramasundaram Pitchiaya

    (University of Michigan
    University of Michigan)

  • Stephanie J. Ellison

    (University of Michigan
    University of Michigan)

  • Jiaqi Shi

    (University of Michigan)

  • Chandan Kumar-Sinha

    (University of Michigan
    University of Michigan)

  • Howard C. Crawford

    (University of Michigan
    University of Michigan)

  • Arul M. Chinnaiyan

    (University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

Abstract

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRASG12C-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.

Suggested Citation

  • Sunita Shankar & Jean Ching-Yi Tien & Ronald F. Siebenaler & Seema Chugh & Vijaya L. Dommeti & Sylvia Zelenka-Wang & Xiao-Ming Wang & Ingrid J. Apel & Jessica Waninger & Sanjana Eyunni & Alice Xu & Ma, 2020. "An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16309-2
    DOI: 10.1038/s41467-020-16309-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-16309-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-16309-2?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:11:y:2020:i:1:d:10.1038_s41467-020-16309-2. 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.