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1. The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma: sVEGFR1, lung tumor progression and anti-angiogenics

Author

Jackeline Agorreta, Thibault Jacquet, Cherine Abou Faycal, Sylvie Gazzeri, Anouk Emadali, Anthony Lucas, Elisabeth Brambilla, Ruben Pio, Nicolas Lemaître, Pedro M Lacal, Nina Lepeltier, Beatrice Eymin, Luis M. Montuenga, Team 'RNA splicing, cell signaling and response to therapies' (U1209 Inserm - CNRS UMR5309 - UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Groupe de Recherche sur le Cancer du Poumon (EA2021), Institut Albert Bonniot, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Team 'Tumor Molecular Pathology and Biomarkers' (U1209 Inserm - CNRS UMR5309 - UGA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Team 'RNA splicing, cell signaling and response to therapies', Team 'Tumor Molecular Pathology and Biomarkers', Department of Histology and Pathology, Team 'Genetics and Epigenetics of Lymphoid Cancers', University of Navarra, Department of Biochemistry and Genetics, Eymin, Beatrice, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, RNA splicing, [SDV]Life Sciences [q-bio], Cell, Angiogenesis Inhibitors, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Proximity ligation assay, Article, Anti-angiogenic therapies, Mice, 03 medical and health sciences, β1 integrin, Carcinoma, Non-Small-Cell Lung, Tumor Cells, Cultured, medicine, Animals, Humans, Protein Isoforms, sVEGFR1, Autocrine signalling, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Vascular Endothelial Growth Factor Receptor-1, business.industry, Integrin beta1, Lung Cancer, Receptor Cross-Talk, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, [SDV] Life Sciences [q-bio], Blot, Autocrine Communication, 030104 developmental biology, medicine.anatomical_structure, Oncology, Cell culture, Carcinoma, Squamous Cell, Disease Progression, Cancer research, Immunohistochemistry, Adenocarcinoma, business, Tyrosine kinase
Abstract

International audience; BACKGROUND:While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known.METHODS:mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples.RESULTS:We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/β1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and β1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC.CONCLUSIONS:Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.

Published
2018
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2. Tonnerre de Brest ! Des Journées de Recherche Respiratoires 2020 pas comme les autres…

Author

Christelle Guibert, Nelly Frossard, C Morelot, membres du comité J R, Philippe Gosset, Mustapha Si-Tahar, Isabelle Vachier, Carole Planès, I Annesi-Maesano, Grégory Bouchaud, Laurent Boyer, Laurent Plantier, Stefan Matecki, Delphine Gras, Myriam Polette, Charles Pilette, Christophe Guignabert, Camille Taillé, B Mari, Philippe Bonniaud, Sylvie Gazzeri, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Team 'RNA splicing, cell signaling and response to therapies' (U1209 Inserm - CNRS UMR5309 - UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR_S 999 «Pulmonary Hypertension: Pathophysiology and Novel Therapies», Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Sorbonne Université - Faculté de médecine [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Faculté de Médecine et Médecine Dentaire [UCLouvain], Université Catholique de Louvain = Catholic University of Louvain (UCL), Groupe Hospitalier Universitaire Paris Seine-Saint-Denis (GHUPSSD), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), CHU Montpellier, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de médecine Pitié Salpétrière, Université de Paris - UFR Médecine [Santé] (UP Médecine), Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - (SLuc) Service de pneumologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité - UFR Médecine [Santé] (UPC UFR Médecine), and Université Paris Cité (UPC)

Subjects
Pulmonary and Respiratory Medicine, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, media_common.quotation_subject, [SDV]Life Sciences [q-bio], 030212 general & internal medicine, Art, Humanities, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, media_common
Abstract

International audience; Tentons un peu d’oublier l’année 2020, mais pas complètement . . . C’est une année qui nousaura conduits à des envies et des visions différentes. Les rencontres conviviales et bien-veillantes qui ponctuent nos journées chaque année au mois d’octobre depuis 2005 n’ontpu se dérouler comme prévues, mais nous étions tous présents pour les 16esJournées deRecherche Respiratoire (J2R) le 16 octobre 2020, bien que devant nos écrans !Nous y avons cru jusqu’au bout et pensions pouvoir bénéficier de la fin de la fenêtreestivale, le programme était prêt et nos hôtes Brestois (nous ne remercierons jamais assezles équipes des Prs Francis Couturaud et Christophe Leroyer) avaient pensé à toutes lessolutions pour maintenir la distanciation, mais force fut de constater fin septembre qu’iln’était plus réaliste de poursuivre l’aventure en présentiel !!!Qu’à cela ne tienne, le plus important était de permettre aux jeunes, dont les résumésavaient suscité suffisamment d’intérêt et d’appétit pour une communication orale, deprésenter leurs travaux. Les J2R 2020 seraient donc organisées en format virtuel. Noustenons à remercier la SPLF pour son soutien logistique qui a permis cette transformation,ainsi que nos sponsors qui nous permettent de faire vivre les J2R depuis 16 ans.C’est ainsi que nos 19 jeunes étudiants chercheurs ont présenté et discuté leurs travauxsous forme de communications orales lors du Webinaire J2R. Tous les thèmes étaient repré-sentés (asthme, BPCO, cancer bronchique, maladies vasculaires, maladies inflammatoirespulmonaires, infectiologie, épidémiologie et la physiologie. . .) et ces communications,comme à l’accoutumée d’excellente qualité, ont pu être écoutées par quelques 135 per-sonnes connectées. Merci à tous des efforts consentis qui ont permis ce succès.

Published
2021
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3. ARF promotes the degradation of the Epidermal Growth Factor Receptor by the lysosome

Author

P. Perron, Anais Beaumont, Sylvie Gazzeri, Celine Barrial, Beatrice Eymin, Anne-Sophie Hatat, Delphine Dayde, Eymin, Beatrice, Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Reading Frames, Lung Neoplasms, EGFR, [SDV]Life Sciences [q-bio], Mutant, Down-Regulation, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Degradation, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Lysosome, medicine, Humans, Epidermal growth factor receptor, Phosphorylation, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Epidermal Growth Factor, biology, Oncogene, ADP-Ribosylation Factors, Wild type, ARF, Cell Biology, ErbB Receptors, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Cell culture, 030220 oncology & carcinogenesis, Mutation, Cancer research, biology.protein, Lung cancer, Lysosomes, Signal Transduction
Abstract

International audience; Epidermal Growth Factor Receptor (EGFR) signaling regulates multiple cellular processes including proliferation , survival and apoptosis, and is attenuated by lysosomal receptor degradation. EGFR is a potent oncogene and activating mutations of EGFR are critical determinants of oncogenic transformation as well as therapeutic targets in non-small cell lung cancer. We previously demonstrated that wild type and mutant EGFRs repress the expression of the ARF tumor suppressor to promote the survival of lung tumor cells. In this study, using transient transfection systems in CHO EGFR-null cells as well as in various lung tumor cell lines carrying wild type or activated mutant EGFR, we show that ARF downregulates the expression of EGFR protein by reducing its half life. In wild type EGFR cells, ARF promotes canonical lysosomal degradation of the receptor through enhanced phosphorylation of EGFR-Y1045 and Cbl-Y731. In contrast, in mutant EGFR cells, ARF induces EGFR degradation by activating a non-canonical AKT-dependent lysosomal pathway. Taken together, these results uncover a feedback loop by which ARF may control EGFR turnover to restrain oncogenic signaling. They also highlight distinct degradation promoting pathways between wild type and mutant EGFRs in response to ARF.

Published
2018
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4. Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI

Author

Laetitia Vanwonterghem, Jean-Luc Coll, Beatrice Eymin, Marie Guerard, Laurence David-Boudet, Sylvie Gazzeri, P. Perron, Anne-Sophie Hatat, Amandine Hurbin, Thomas Robin, Benoit Busser, Sylvie Lantuejoul, Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Team 'Cancer targets and experimental therapeutics', Centre Hospitalier Universitaire [Grenoble] (CHU), Eymin, Beatrice, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Apoptosis, MESH: EGFR-TKI, IGF1R, Lung cancer, Nuclear trafficking, Resistance, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Amphiregulin, Receptor tyrosine kinase, Receptor, IGF Type 1, 03 medical and health sciences, Gefitinib, Epidermal growth factor, Cell Line, Tumor, medicine, Humans, skin and connective tissue diseases, Protein Kinase Inhibitors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Insulin-like growth factor 1 receptor, Cell Nucleus, biology, Chemistry, Receptors, Somatomedin, Cell Cycle Checkpoints, medicine.disease, Adenocarcinoma, Mucinous, Xenograft Model Antitumor Assays, respiratory tract diseases, 3. Good health, [SDV] Life Sciences [q-bio], body regions, Protein Transport, Cell nucleus, 030104 developmental biology, medicine.anatomical_structure, Oncology, A549 Cells, Drug Resistance, Neoplasm, Cancer research, biology.protein, Signal transduction, Signal Transduction, medicine.drug
Abstract

International audience; Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xeno-grafts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-b1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer.

Published
2018
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5. The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma

Author

Faycal, Cherine, Brambilla, Elisabeth, Agorreta, Jackeline, Lepeltier, Nina, Jacquet, Thibault, Lemaître, Nicolas, Emadali, Anouk, Lucas, Anthony, Lacal, Pedro, Montuenga, Luis, Pio, Ruben, Gazzeri, Sylvie, Eymin, Béatrice, Eymin, Beatrice, Team 'RNA splicing, cell signaling and response to therapies' (U1209 Inserm - CNRS UMR5309 - UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Groupe de Recherche sur le Cancer du Poumon (EA2021), Institut Albert Bonniot, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Team 'Tumor Molecular Pathology and Biomarkers' (U1209 Inserm - CNRS UMR5309 - UGA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Anti-angiogenic therapies, [SDV] Life Sciences [q-bio], RNA splicing, β1 integrin, [SDV]Life Sciences [q-bio], Lung Cancer, sVEGFR1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; BACKGROUND:While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known.METHODS:mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples.RESULTS:We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/β1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and β1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC.CONCLUSIONS:Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.

Published
2018
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6. VEGF165b, a splice variant of VEGF-A, promotes lung tumor progression and escape from anti-angiogenic therapies through a β1 integrin/VEGFR autocrine loop

Author

Asma Boudria, Christian Brambilla, Nicolas Lemaître, Cherine Abou Faycal, Elisabeth Brambilla, Beatrice Eymin, Sylvie Gazzeri, Corinne Albiges-Rizo, Sandra Manet, Tao Jia, Chloé Didier, Denis Moro-Sibilot, Anne-Claire Toffart, Eva Faurobert, Michelle Keramidas, Jean-Luc Coll, Véronique Josserand, Stephanie Gout, Eymin, Beatrice, Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Team 'Cancer targets and experimental therapeutics', Team 'Tumor Molecular Pathology and Biomarkers', Team 'Cell Adhesion Dynamics and Differentiation', Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), This work was supported by the Comité Départemental Isère and Comité Départemental Savoie de la Ligue Nationale contre le Cancer, by the INCa/DHOS (Appel d’Offre Recherche Translationnelle 2010), by the Fondation de France (Projet Grande Ampleur 2011), by ROCHE fellowship (Bourse de Recherche Fondamentale), by the Fondation ARC pour la Recherche Contre le Cancer and by Fonds de dotation AGIR pour les Maladies Chroniques. Stephanie Gout and Tao Jia were supported by a post-doctoral fellowship from the Fondation ARC pour la Recherche Contre le Cancer. Asma Boudria was supported by the Ministere de l’Education et de la Recherche Algerien (program PROFAS) and by the Fondation pour La Recherche Médicale. Cherine Abou Faycal was supported by the Ligue Nationale Contre Le Cancer. The CAR team is supported by the Ligue Nationale Contre Le Cancer (Equipe labellisée Ligue 2014)., Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Cancer Research, Angiogenesis, [SDV]Life Sciences [q-bio], Cell, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, splice, Autocrine signalling, Lung cancer, Receptor, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene knockdown, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Adenocarcinoma
Abstract

International audience; Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGFxxx and VEGFxxxb families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGFxxx splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described. The role of VEGFxxxb isoforms is less well known, but they have been shown to inhibit VEGFxxx-mediated angiogenesis, while being partial or weak activators of VEGFR receptors in endothelial cells. On the opposite, their role on tumor cells expressing VEGFRs at their surface remains largely unknown. In this study, we find elevated levels of VEGF165b, the main VEGFxxxb isoform, in 36% of non-small cell lung carcinoma (NSCLC), mainly lung adenocarcinoma (46%), and show that a high VEGF165b/VEGF165 ratio correlates with the presence of lymph node metastases. At the molecular level, we demonstrate that VEGF165b stimulates proliferation and invasiveness of two lung tumor cell lines through a VEGFR/β1 integrin loop. We further provide evidence that the isoform-specific knockdown of VEGF165b reduces tumor growth, demonstrating a tumor-promoting autocrine role for VEGF165b in lung cancer cells. Importantly, we show that bevacizumab, an anti-angiogenic compound used for the treatment of lung adenocarcinoma patients, increases the expression of VEGF165b and activates the invasive VEGFR/β1 integrin loop. Overall, these data highlight an unexpected role of the VEGF165b splice variant in the progression of lung tumors and their response to anti-angiogenic therapies.

Published
2018
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7. Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

Author

Dayde, Delphine, Guerard, Marie, Perron, Pascal, Hatat, Anne-Sophie, Barrial, Celine, Eymin, Béatrice, gazzeri, sylvie, Institut Albert Bonniot, Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U1209, Institute for Advanced Biosciences, and gazzeri, sylvie

Subjects
[SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2015

8. Loss of heterozygosity at the RB locus correlates with loss of RB protein in primary malignant neuro-endocrine lung carcinomas

Author

Elisabeth Brambilla, Denis Moro, Alim-Louis Benabid, Christian Brambilla, Isabelle Bolon, Pascal Perron, Sylvie Gazzeri, Valérie Gouyer, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), INSERM U1209, Institute for Advanced Biosciences, Groupe de Recherche sur le Cancer du Poumon (EA2021), Institut Albert Bonniot, Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Clinique de pneumologie, CHU Grenoble, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)

Subjects
Cancer Research, Heterozygote, Lung Neoplasms, [SDV]Life Sciences [q-bio], Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Retinoblastoma Protein, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Humans, Allele, Genes, Retinoblastoma, Gene, 030304 developmental biology, 0303 health sciences, Lung Neoplasms/genetics/metabolism, Phenotype, Molecular biology, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Neuroendocrine Tumors, Oncology, Retinoblastoma Protein/analysis/genetics/metabolism, Neuroendocrine Tumors/genetics/metabolism, 030220 oncology & carcinogenesis, biology.protein, Restriction fragment length polymorphism, Antibody, Gene Deletion
Abstract

International audience; RB protein expression and loss of heterozygosity (LOH) in the RB gene were studied in 77 primary lung carcinomas of all histological types. RB protein expression was studied by immunohistochemistry with 3 anti-RB antibodies, and was found altered in 23/29 (79%) neuro-endocrine (NE) carcinomas and in 18/48 (37%) non-NE carcinomas. RB gene allele status was studied with 3 probes detecting RFLP in RB locus. Fifty-five patients were informative, and loss of heterozygosity was detected in 29 (52%) of the corresponding tumors with 1 of the 3 probes used; 89% of the informative NE carcinomas, excluding carcinoids, and only 13% of the non-NE carcinomas exhibited LOH and loss of RB-protein expression. LOH at the RB locus was strongly correlated with the absence of RB protein in malignant NE carcinomas, and this association was strongly correlated with the neuro-endocrine phenotype. Inactivation of the RB protein in primary NE carcinomas, excluding carcinoids, therefore seems to imply in the majority of cases the mutation of one allele and loss of the remaining allele of the RB gene, leading to loss of RB-protein expression. In contrast, RB-protein expression was independent of allele status in non-NE carcinomas and carcinoids.

Published
1994
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9. p53 genetic abnormalities andmyc activation in human lung carcinoma

Author

gazzeri, sylvie, Brambilla, Elisabeth, Caron de Fromentel, C, Gouyer, Valérie, Moro, Denis, Perron, Pascal, Berger, François, Brambilla, Christian, De Fromentel, Claude Caron, INSERM U1209, Institute for Advanced Biosciences, Groupe de Recherche sur le Cancer du Poumon (EA2021), Institut Albert Bonniot, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Clinique de pneumologie, CHU Grenoble, Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Cancer Research, Lung Neoplasms, Tumor suppressor gene, Transcription, Genetic, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Genes, myc, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, MYC Gene Amplification, Carcinoma, medicine, Humans, Northern blot, RNA, Messenger, Lung cancer, 030304 developmental biology, 0303 health sciences, Epithelioma, Base Sequence, Gene Amplification, medicine.disease, Genes, p53, Prognosis, 3. Good health, respiratory tract diseases, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Carcinogenesis, Immunostaining
Abstract

International audience; p53 mutations and myc gene amplification and expression were studied in 119 lung carcinomas of all histological types. A mutant p53 immunophenotype was previously found in 47% of these tumors by immunohistochemical analysis. Seven cases exhibited p53 genomic rearrangements on Southern blots. Elevated levels of p53 transcript were found in 12 carcinomas (10%) and decreased levels in 27 carcinomas (23%) on Northern blots. In most of the cases, low levels of transcript were associated with negative immunostaining, whereas elevated levels of mRNA were related to positive immunostaining (mutant immunophenotype). p53 RT/PCR analysis in 10 tumors with absence of transcript on Northern blots revealed only weak or absent expression of normal and/or altered size transcripts. These abnormal transcripts showed deletions, insertions or splicing abnormalities. Taken together, p53 abnormalities were found in 66% of lung carcinomas [52% of neuroendocrine (NE) carcinomas and 75% of NSCLC]. c-myc was found to be activated in 24% (10/42) of these NE and in 48% (33/69) of these NSCLC carcinomas using Southern- and Northern-blot techniques. In addition, L- and N-myc genes were also activated in 26% (10/42) of NE carcinomas. No correlation was found between p53 mutations and myc activation in SCLC or in NSCLC, but their association was significantly more frequent in NSCLC than in SCLC. These results indicate that the p53-positive immunophenotype uncovers the occurrence of p53 point mutations in lung cancer and that p53 and c-myc gene alterations are important but represent independent occurrences in the development of lung tumors.

Published
1994
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12. Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer.

Author

Hatat AS, Benoit-Pilven C, Pucciarelli A, de Fraipont F, Lamothe L, Perron P, Rey A, Levra MG, Toffart AC, Auboeuf D, Eymin B, and Gazzeri S

Subjects
Autophagy, Autophagy-Related Proteins pharmacology, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, EGF Family of Proteins pharmacology, EGF Family of Proteins therapeutic use, ErbB Receptors metabolism, Gefitinib pharmacology, Gefitinib therapeutic use, Humans, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
Abstract

Despite the initial efficacy of using tyrosine kinase inhibitors of epidermal growth factor receptors (EGFR-TKIs) for treating patients with non-small cell lung cancer (NSCLC), resistance inevitably develops. Recent studies highlight a link between alternative splicing and cancer drug response. Therefore, we aimed to identify deregulated splicing events that play a role in resistance to EGFR-TKI. By using RNA sequencing, reverse-transcription PCR (RT-PCR), and RNA interference, we showed that overexpression of a splice variant of the autophagic gene ATG16-L1 that retains exon 8 and encodes the β-isoform of autophagy-related protein 16-1 (ATG16-L1 β) concurs acquired resistance to EGFR-TKI in NSCLC cells. Using matched biopsies, we found increased levels of ATG16-L1 β at the time of progression in 3 of 11 NSCLC patients treated with EGFR-TKI. Mechanistically, gefitinib-induced autophagy was impaired in resistant cells that accumulated ATG16-L1 β. Neutralization of ATG16-L1 β restored autophagy in response to gefitinib, induced apoptosis, and inhibited the growth of in ovo tumor xenografts. Conversely, overexpression of ATG16-L1 β in parental sensitive cells prevented gefitinib-induced autophagy and increased cell survival. These results support a role of defective autophagy in acquired resistance to EGFR-TKIs and identify splicing regulation of ATG16-L1 as a therapeutic vulnerability that could be explored for improving EGFR-targeted cancer therapy., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Published
2022
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13. Splice Variants of the RTK Family: Their Role in Tumour Progression and Response to Targeted Therapy.

Author

Abou-Fayçal C, Hatat AS, Gazzeri S, and Eymin B

Subjects
Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Biomarkers, Disease Progression, ErbB Receptors blood, ErbB Receptors genetics, ErbB Receptors metabolism, Gene Expression Regulation, Neoplastic, Humans, Molecular Targeted Therapy, Neoplasms diagnosis, Neoplasms drug therapy, Neoplasms metabolism, Prognosis, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, RNA Precursors genetics, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases metabolism, Vascular Endothelial Growth Factor Receptor-1 genetics, Alternative Splicing, Multigene Family, Neoplasms genetics, Receptor Protein-Tyrosine Kinases genetics
Abstract

Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic properties have been reported in various tumour types. Numerous RTK-targeted therapies have been developed to counteract this hyperactivation. Alternative splicing of pre-mRNA has recently emerged as an important contributor to cancer development and tumour maintenance. Interestingly, RTKs are alternatively spliced. However, the biological functions of RTK splice variants, as well as the upstream signals that control their expression in tumours, remain to be understood. More importantly, it remains to be determined whether, and how, these splicing events may affect the response of tumour cells to RTK-targeted therapies, and inversely, whether these therapies may impact these splicing events. In this review, we will discuss the role of alternative splicing of RTKs in tumour progression and response to therapies, with a special focus on two major RTKs that control proliferation, survival, and angiogenesis, namely, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-1 (VEGFR1).

Published
2017
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