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

Angiolini, Francesca; Irimia Martínez, Manuel; Chigna, Claudia

doi:http://dx.doi.org/10.7554/eLife.44305

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

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Angiolini F, Belloni E, Giordano M, Campioni M, Forneris F, Paronetto MP. A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing. eLife. 2019;8:e44305. DOI: 10.7554/eLife.44305

Abstract

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.