A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-DTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-DTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-DTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-DTM are overexpressed in the vasculature of ovarian cancer, where L1-DTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-DTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-DTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.