0170 : VEGF-D translational regulations promotes tumor lymphatic vessels plasticity

The lymphatic vasculature has a major role in physiology. It drains the interstitial fluids and performs immune surveillance by transporting immunity cells. The lymphatic vessels are also involved in pathological conditions such as chronic inflammatory diseases, lymphedema and cancer. Lymphangiogenesis, the growth of new lymphatic vessels, is induced by the lymphangiogenic growth factors VEGF-C and VEGF-D. Recent studies suggest that VEGF-D is also involved in lymphatic dilatation through prostaglandin signaling pathways. In this study, we demonstrated the molecular mechanism involved in lymphatic dilatation. We identified a stress-induced translational regulation of VEGF-D expression through an IRES activation under heat shock conditions. We demonstrated that VEGF-D IRES activity was dependent of prostaglandin pathway as Cox-2 inhibitors are able to abolish the IRES-promoted VEGF-D protein synthesis, and lymphatic vessels dilatation. Using plasmon surface resonance on biotinylated VEGF-D mRNA coupled to mass spectrometry, we identified the IRES transacting factor (ITAF) that allows the recruitment of the ribosome to promote VEGF-D translational initiation: the Nucleolin. Our results bring new insights on the VEGF-D regulation and on the lymphatic vessels plasticity. As lymphatic vessels play a crucial role in inflammation by performing immune cells tissue trafficking, understanding the regulations of lymphatic vasodilatation is a crucial step toward an innovative inflammatory disease therapy.