SUMMARY This project is designed to test a novel hypothesis that cancer cells communicate with the host via C5a/C5aR- induced systemic SK1/S1P, which then promotes tumor metastasis, and that inhibition of systemic S1P/C5aR signaling suppresses metastasis. To test this hypothesis, three Specific Aims are proposed: Aim 1 is designed to define the roles and mechanisms of cancer cell-induced vascular endothelial cell complement signaling and systemic SK1/S1P in the regulation of tumor metastasis. Aim 2 is designed to determine the down-stream mechanisms by which cancer cell-induced systemic SK-1/S1P promotes tumor metastasis. In this Aim, our main goal is to test our hypothesis that cancer cell-induced systemic SK1/S1P inhibits the expression of a master suppressor of metastasis (BRMS1) via S1PR2 signaling in cancer cells, inducing tumor metastasis. Aim 3 is designed to determine the therapeutic efficacy of targeting systemic S1P and/or C5a signaling for the attenuation of tumor metastasis. In this Aim, our main goal is to test a novel hypothesis that inhibition of systemic C5aR/SK1/S1P signaling will inhibit tumor metastasis via activation of tumor BRMS1. These studies will help uncover how cancer cells communicate with the host via SK1/S1P and complement signaling to regulate tumor metastasis, leading to the development of novel therapeutic strategies for the inhibition of tumor growth or metastasis. In this project, we will also determine if the elevation of systemic S1P/C5a in patients with advanced solid tumors will provide novel serum markers for monitoring response to therapy and/or early detection of progression to metastasis.