Tumor growth and metastasis depend on complex involvement of growth factors, angiogenesis and escape to the immune system surveillance. Better understandings of these processes are required to develop more efficient cancer therapies. Autotaxin (ATX) is a secreted glycoprotein by tumor cells which mediate pro-metastasic and pro-angiogenic activities. Its lysophospholipase D (lysoPLD) activity allows the synthesis of two biological lipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are linked to both cancer progression, metastasis and control of immune system through lymphocytes and dendritic cells (DC). However, the roles of ATX, LPA and S1P in cancer are poorly understood. We will first quantify the expression of ATX/lysoPLD activity from human libraries of cDNA, biological fluids and tissue microarrays, from patients with metastatic and non metastatic breast cancers. We will study the effect of ATX silencing on mouse breast 4T1 tumor cells and de novo expression of wild type ATX and a lysoPLD-deficient ATX mutant on human MDA-BO2 breast cancer cells. We will characterize in vitro the role of ATX on breast cancer cell functions and analyze the biological activity of LPA and S1P on DC (differentiation, IFN?/IL-12 production). We will analyze the role of ATX in vivo on a syngenic mouse model in tumor growth, spontaneous metastasis, in immune infiltrate composition, and anti-tumor immune response. We will also study the effect of functional blocking of ATX lysoPLD activity on human MDA-BO2 cells in a nude mouse model for tumor growth and bone metastasis formation as well as in functional human DC alteration in SCID/NOD/B2-/- mice model of human breast tumor/DC interaction in vivo. Along with the role of ATX in breast cancer growth and metastasis, this project will determine its role in the control of immunity by breast cancer cells. We will also define whether ATX is a target for the design of new therapies for patients with breast cancers.