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-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.
Competing Interests: EB, MG, MC, FF, PP, ML, CB, DP, AD, CG, GJ, CL, GB, SF, MM, MI, CG, RG, DN, DG No competing interests declared, JM, JS Affiliated with Gene Tools, LLC. Funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. ED Reviewing editor, eLife, CG Consultant for Gene-Tools, LLC. Funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
(© 2019, Angiolini et al.)