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-ΔTM. 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-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC, projects IG-17395 to CG, IG-14622 to UC, IG-18683 to ED and IG-18853 to RG, IG-19919 to DG), Worldwide Cancer Research (formerly known as Association for International Cancer Research; AICR 10–0091 to UC), the European Research Council (ERC) under the European Union's Horizon 2020 program (ERC-StG-LS2-637591 to MI) and the Spanish Ministerio de Economía y Competitividad (BFU2017-89201-P to MI). EB, FA and ADM were supported by AIRC - FIRC ITALY postdoctoral fellowships. MG was supported by a fellowship from Fondazione IEO-CCM. Research in FF laboratory is supported by The Giovanni Armenise-Harvard Foundation, and by the Italian Ministry for Education, University and Research (MIUR): Programma Giovani Ricercatori "Rita Levi-Montalcini" and Dipartimenti di Eccellenza Program (2018–2022) - Dept. of Biology and Biotechnology "L. Spallanzani", University of Pavia. AC is supported by a Marie Curie Individual Fellowship from the Horizon 2020 EU Program (Grant agreement n. 745934 – COTETHERS).