IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v586y2020i7828d10.1038_s41586-020-2774-y.html
   My bibliography  Save this article

Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis

Author

Listed:
  • Bernardo Tavora

    (The Rockefeller University)

  • Tobias Mederer

    (The Rockefeller University)

  • Kai J. Wessel

    (The Rockefeller University)

  • Simon Ruffing

    (The Rockefeller University)

  • Mahan Sadjadi

    (The Rockefeller University)

  • Marc Missmahl

    (The Rockefeller University)

  • Benjamin N. Ostendorf

    (The Rockefeller University)

  • Xuhang Liu

    (The Rockefeller University)

  • Ji-Young Kim

    (The Rockefeller University)

  • Olav Olsen

    (The Rockefeller University)

  • Alana L. Welm

    (University of Utah)

  • Hani Goodarzi

    (University of California, San Francisco)

  • Sohail F. Tavazoie

    (The Rockefeller University)

Abstract

Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active ‘instructive’ roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.

Suggested Citation

  • Bernardo Tavora & Tobias Mederer & Kai J. Wessel & Simon Ruffing & Mahan Sadjadi & Marc Missmahl & Benjamin N. Ostendorf & Xuhang Liu & Ji-Young Kim & Olav Olsen & Alana L. Welm & Hani Goodarzi & Soha, 2020. "Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis," Nature, Nature, vol. 586(7828), pages 299-304, October.
  • Handle: RePEc:nat:nature:v:586:y:2020:i:7828:d:10.1038_s41586-020-2774-y
    DOI: 10.1038/s41586-020-2774-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2774-y
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-2774-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
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Roberta Piras & Emily Y. Ko & Connor Barrett & Marco Simone & Xianzhi Lin & Marina T. Broz & Fernando H. G. Tessaro & Mireia Castillo-Martin & Carlos Cordon-Cardo & Helen S. Goodridge & Dolores Vizio , 2022. "circCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    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:nature:v:586:y:2020:i:7828:d:10.1038_s41586-020-2774-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.