Bernardo Tavora

Laboratory of Systems Cancer Biology, Rockefeller University, New York.

Endothelial-Tumor Cell Interactions in Metastasis

Tumour blood vessels not only provide nutrients and oxygen to cancer cells but also allow dissemination of cancer cell to distant organs. Recent studies have suggested that endothelial cells may actually play regulatory roles in driving cancer progression. Firstly, cancer cells with high propensity to metastasize exhibit enhanced capacity for endothelial recruitment. Secondly, cancer-endothelial interactions have been shown to promote metastatic colonization.

To identify endothelial-derived factors that may instructively drive cancer metastasis, we sought to identify secreted factors that are induced in the endothelium of tumors that progress to metastatic disease. In-vivo endothelial-specific ribosomal tagging and ribosome-associated mRNA-sequencing from highly metastatic and poorly metastatic tumours identified an axon-guidance gene (Slit2) as an endothelial derived (angiocrine) factor that acts on tumor cells to drive tumor migration towards endothelium, intravasation, and metastasis. Endothelial-specific deletion of Slit2 in mice (Slit2fl/fl;VecadCreERT) inhibited metastatic dissemination by breast (4T1 and MMTV-PyMT) and lung cancers (Lewis Lung Carcinoma) without affecting primary tumor growth or tumour angiogenesis. Endothelial-derived Slit2 is detected by tumoural Robo1 receptors, driving cancer cell migration towards the endothelial Slit2 source. Consistent with these observations, increased Slit2 expression in the endothelial relative to the tumoural compartment significantly associated with human cancer progression stage.

Mechanistically, we implicate extracellular RNA release by metastatic tumours as the signal that induces Slit2 expression by acting on endothelial toll-like receptors. Our findings support a new model whereby tumoural extracellular RNA activates expression of vascular Slit2, which acts as a pro-metastatic factor. Thus, cancer cells take advantage of innate RNA sensing to induce a chemotactic signaling pathway in the endothelium facilitating tumor cell migration towards endothelial cells and into the blood stream, where they can be transported to distant organs to form lethal metastases. 
 

Contact : Isabelle Saves (Isabelle.Saves@ipbs.fr)

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