Journal Article

Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis

Welm, Alana L., Mederer, Tobias, Missmahl, Marc, Tavora, Bernardo, Ruffing, Simon, Liu, Xuhang, Wessel, Kai J., Olsen, Olav, Ostendorf, Benjamin N., Goodarzi, Hani, Tavazoie, Sohail F., Kim, Ji-Young, Sadjadi, Mahan

2020

Overview

Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer 1 . 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. Expression of the axon-guidance gene Slit2 in endothelium, induced by endothelial sensing of tumour-derived double-stranded RNA, promotes metastatic dissemination in mouse models of breast and lung cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 14/19 / 45/91 / 59/5 / 631/67/322 / 631/67/327 / 631/67/70 / 64/60 / Angiogenesis / Animal models / Animals / Blood vessels / Breast cancer / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Chemotaxis / Disease Models, Animal / Disease Progression / Double-stranded RNA / Endothelial cells / Endothelial Cells - metabolism / Endothelium / Endothelium - metabolism / Female / Gene expression / Humanities and Social Sciences / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Lung cancer / Lung diseases / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Lymphatic system / Male / Melanoma / Metastases / Metastasis / Mice / multidisciplinary / Neoplasm Metastasis - genetics / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Nutrients / Oxygen / Proteins / Receptors / Receptors, Immunologic - genetics / Receptors, Immunologic - metabolism / Ribonucleic acid / Ribosomes / RNA / RNA, Double-Stranded / Rodents / Roundabout Proteins / Science / Science (multidisciplinary) / Signal Transduction / TLR3 protein / Toll-Like Receptor 3 - deficiency / Toll-Like Receptor 3 - genetics / Toll-Like Receptor 3 - metabolism / Toll-like receptors / Tumor Cells, Cultured / Tumors