IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-17549-y.html
   My bibliography  Save this article

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

Author

Listed:
  • Léo Aubert

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Neethi Nandagopal

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Zachary Steinhart

    (University of Toronto)

  • Geneviève Lavoie

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Sami Nourreddine

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Jacob Berman

    (University of Toronto)

  • Marc K. Saba-El-Leil

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • David Papadopoli

    (McGill University)

  • Sichun Lin

    (University of Toronto)

  • Traver Hart

    (University of Texas)

  • Graham Macleod

    (University of Toronto)

  • Ivan Topisirovic

    (McGill University)

  • Louis Gaboury

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    Université de Montréal)

  • Christoph J. Fahrni

    (Georgia Institute of Technology)

  • Daniel Schramek

    (University of Toronto
    University of Toronto)

  • Sylvain Meloche

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    Université de Montréal)

  • Stephane Angers

    (University of Toronto
    University of Toronto)

  • Philippe P. Roux

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    Université de Montréal)

Abstract

Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms.

Suggested Citation

  • Léo Aubert & Neethi Nandagopal & Zachary Steinhart & Geneviève Lavoie & Sami Nourreddine & Jacob Berman & Marc K. Saba-El-Leil & David Papadopoli & Sichun Lin & Traver Hart & Graham Macleod & Ivan Top, 2020. "Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17549-y
    DOI: 10.1038/s41467-020-17549-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-17549-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-17549-y?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_s41467-020-17549-y. 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.