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

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dc.contributor.author	Angiolini, Francesca
dc.contributor.author	Irimia, Manuel
dc.contributor.author	Chigna, Claudia
dc.date	2019
dc.identifier.citation	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. pii: e44305. DOI 10.7554/eLife.44305
dc.identifier.citation	2050-084X
dc.identifier.citation	http://dx.doi.org/10.7554/eLife.44305
dc.identifier.uri	http://hdl.handle.net/10230/36982
dc.format	application/pdf
dc.language.iso	eng
dc.publisher	eLife
dc.relation	Elife. 2019; 8. pii: e44305
dc.relation	info:eu-repo/grantAgreement/EC/H2020/637591
dc.relation	info:eu-repo/grantAgreement/EC/H2020/745934
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	© Angiolini et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
dc.rights	http://creativecommons.org/licenses/by/4.0/
dc.title	A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/publishedVersion
dc.description.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.
dc.description.abstract	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).

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