eLife (Mar 2019)
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 Chiapparino,
- Carmen Ghilardi,
- Raffaella Giavazzi,
- Daniel Nyqvist,
- Davide Gabellini,
- Elisabetta Dejana,
- Ugo Cavallaro,
- Claudia Ghigna
Affiliations
- Francesca Angiolini
- Unit of Gynecological Oncology Research, Program of Gynecological Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Elisa Belloni
- ORCiD
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
- Marco Giordano
- ORCiD
- Unit of Gynecological Oncology Research, Program of Gynecological Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Matteo Campioni
- The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
- Federico Forneris
- ORCiD
- The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
- Maria Paola Paronetto
- Department of Movement, Human and Health Sciences, Università degli Studi di Roma "Foro Italico", Rome, Italy
- Michela Lupia
- Unit of Gynecological Oncology Research, Program of Gynecological Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Chiara Brandas
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
- Davide Pradella
- ORCiD
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy; Università degli Studi di Pavia, Pavia, Italy
- Anna Di Matteo
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
- Costanza Giampietro
- ORCiD
- FIRC Institute of Molecular Oncology, Milan, Italy
- Giovanna Jodice
- Molecular Medicine Program, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Chiara Luise
- Molecular Medicine Program, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Giovanni Bertalot
- ORCiD
- Molecular Medicine Program, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Stefano Freddi
- Molecular Medicine Program, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Matteo Malinverno
- FIRC Institute of Molecular Oncology, Milan, Italy
- Manuel Irimia
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
- Jon D Moulton
- ORCiD
- Gene Tools LLC, Philomath, United States
- James Summerton
- Gene Tools LLC, Philomath, United States
- Antonella Chiapparino
- The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
- Carmen Ghilardi
- Laboratory of Biology and Treatment of Metastasis, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
- Raffaella Giavazzi
- Laboratory of Biology and Treatment of Metastasis, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
- Daniel Nyqvist
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- Davide Gabellini
- ORCiD
- Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Elisabetta Dejana
- FIRC Institute of Molecular Oncology, Milan, Italy; Rudbeck Laboratory and Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Ugo Cavallaro
- ORCiD
- Unit of Gynecological Oncology Research, Program of Gynecological Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Claudia Ghigna
- ORCiD
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
- DOI
- https://doi.org/10.7554/eLife.44305
- Journal volume & issue
-
Vol. 8
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.
Keywords
