Molecular analysis of tumor-vessel interactions during tumor progression

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Metastasis results from an intricate bi-directional communication of tumor cells (TC) with cells of the blood and lymphatic vessel wall (EC). Metastatic TC induce angiogenesis, intravasate vessels, travel in the circulation to distant sites, adhere to EC in secondary organs to eventually extravasate and to establish distant metastases. Beyond the induction of angiogenesis, the mechanisms of these multiple TC and EC interactions are poorly understood at the molecular level. We have in previous work characterized the expression, cellular functions and the role during tumor progression and angiogenesis of the EphB4 receptor tyrosine kinase and its corresponding ephrinB2 ligand. These experiments have beyond the established roles of the EphB/ephrinB system for angiogenesis and arteriovenous differentiation provided evidence for a role of EphB receptors and ephrinB ligands in controlling adhesive TC-EC interactions. Based on these findings and additional preliminary data, the present project is aimed at systematically studying in cellular and in vivo experiments adhesive EphB/ephrinB interactions between tumor cells and endothelial cells that control tumor progression and metastasis. The experiments are aimed at shedding light into a novel TC-EC adhesion mechanism. The established platform of relevant cellular and in vivo assays will also be exploited to study other adhesive mechanisms that may be involved in TC metastatic dissemination. Collectively, the experiments will contribute to a better mechanistic understanding of a key step of the metastatic cascade.