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

Francesca Angiolini, Elisa Belloni, Marco Giordano, Matteo Campioni, Federico Forneris, Maria Paola Paronetto, Michela Lupia, Chiara Brandas, Davide Pradella, Anna Di Matteo, Costanza Giampietro, Giovanna Jodice, Chiara Luise, Giovanni Bertalot, Stefano Freddi, Matteo Malinverno, Manuel Irimia, Jon D. Moulton, James Summerton, Antonella ChiapparinoCarmen Ghilardi, Raffaella Giavazzi, Daniel Nyqvist, Davide Gabellini, Elisabetta Dejana, Ugo Cavallaro, Claudia Ghigna

Research output: Contribution to journalArticle

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-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.

Original languageEnglish
Article numbere44305
JournaleLife
Volume8
DOIs
Publication statusPublished - Mar 2019

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Angiolini, F., Belloni, E., Giordano, M., Campioni, M., Forneris, F., Paronetto, M. P., Lupia, M., Brandas, C., Pradella, D., Di Matteo, A., Giampietro, C., Jodice, G., Luise, C., Bertalot, G., Freddi, S., Malinverno, M., Irimia, M., Moulton, J. D., Summerton, J., ... Ghigna, C. (2019). A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing. eLife, 8, [e44305]. https://doi.org/10.7554/eLife.44305