Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis
| Autor: | Alana L. Welm, Bernardo Tavora, Olav Olsen, Mahan Sadjadi, Ji-Young Kim, Kai J. Wessel, Xuhang Liu, Marc Missmahl, Sohail F. Tavazoie, Simon Ruffing, Tobias Mederer, Hani Goodarzi, Benjamin N. Ostendorf |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Lung Neoplasms Metastasis Mice Double-Stranded 0302 clinical medicine Immunologic Receptors Tumor Cells Cultured 2.1 Biological and endogenous factors Receptors Immunologic Neoplasm Metastasis Aetiology Cancer Multidisciplinary Cultured Chemotaxis Tumor Cells medicine.anatomical_structure 030220 oncology & carcinogenesis Disease Progression Intercellular Signaling Peptides and Proteins Female Signal transduction Signal Transduction Endothelium General Science & Technology Breast Neoplasms Nerve Tissue Proteins Biology Article 03 medical and health sciences Downregulation and upregulation Breast Cancer medicine Genetics Animals Humans RNA Double-Stranded Animal Intravasation Endothelial Cells medicine.disease Toll-Like Receptor 3 Disease Models Animal 030104 developmental biology Cancer cell TLR3 Disease Models Cancer research RNA |
| Zdroj: | Nature, vol 586, iss 7828 Nature |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|