Screening of anti-metastasis drugs by targeting angiopellosis and cancer cluster extravasation

Metastasis accounts for 90% of cancer-related deaths. Extravasation is a necessary step for cancer metastasis. Currently, there are no drugs that specially target extravasation. Most cancer therapies target either proliferation or angiogenesis. We previously identified "angiopellosis" as the dominant mechanism by which vascular endothelial cells undergo conformational changes and actively "push" circulating cancer cells out of blood vessels. In this study, we developed an image-based high-throughput drug screening assay by coculturing cancer membrane-coated spheres with endothelial monolayers. Through this platform, we identified Bay 61-3606 as a lead angiopellosis inhibitor. Bay 61-3606 substantially reduced cancer cluster extravasation, an activity solely supported by angiopellosis and associated with higher metastatic potential, in both zebrafish and mouse models. Furthermore, Bay 61-3606 decreased distant metastases in murine models of lung carcinoma and triple-negative breast cancer. Mechanistically, Bay 61-3606 targeted the c-Jun amino-terminal kinase signaling pathway, down-regulating COL8A1 expression in endothelial cells and impairing the angiopellosis process.