Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis

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 and Sohail F. Tavazoie ()
Additional contact information
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

Nature, 2020, vol. 586, issue 7828, 299-304

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2774-y

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