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1. FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their coexpression may predict FGFR-targeted therapy efficacy

Author

Santiago García, Luis Paz-Ares, Fernando Lopez-Rios, Jon Zugazagoitia, Sonia Molina-Pinelo, Laura Ojeda, Irene Ferrer, Sandra Muñoz-Galván, Elizabeth Guruceaga, Luis M. Montuenga, Silvestre Vicent, Cristina Cirauqui, Álvaro Quintanal-Villalonga, Amancio Carnero, Ángela Marrugal, [Quintanal-Villalonga,Á, Ferrer,I, Cirauqui,C, Marrugal,Á, Ojeda,L, García,S, Zugazagoitia,J, Paz-Ares,L] H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigacion Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. [Quintanal-Villalonga,Á] Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [Ferrer,I, Muñoz-Galván,S, Lopez-Rios,F, Montuenga,L, Vicent,S, Molina-Pinelo,S, Carnero,A, Paz-Ares,L] CIBERONC, Madrid, Spain. [Guruceaga,E] Bioinformatics Unit, Centre for Applied Medical Research (CIMA), Pamplona, Spain. [Guruceaga,E] PROTEORED, Madrid, Spain. [Zugazagoitia,J, Paz-Ares,L] Medical Oncology Department, Hospital Universitario Doce de Octubre. Madrid, Spain. [Muñoz-Galván,S, Carnero,A] Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain. [Lopez-Rios,F] Laboratorio de Dianas Terapeuticas, Hospital Universitario HM Sanchinarro, Madrid, Spain. [Montuenga,L, Vicent,S] Program in Solid Tumors, Centre for Applied Medical Research (CIMA), Pamplona, Spain. [Montuenga,L, Vicent,S] Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain. [Montuenga,L, Vicent,S] IdiSNA, Navarra Institute for Health Research, Pamplona, SPAIN. [Paz-Ares,L] Medical School, Universidad Complutense, Madrid, Spain., This work was funded by the Community of Madrid, the ISCIII cofunded by FEDER from Regional Development European Funds (European Union), the Spanish Ministry of Economy and Competitiveness, the Mutua Madrilena Foundation, the Ministry of Health and Social ~ Welfare of Junta de Andalucía, the AECC scientific foundation and the Spanish Ministry of Education, Culture and Sport. L.P.A. was funded by the Community of Madrid, CAM, (B2017/BMD3884), ISCIII (PIE15/00076, PI17/00778 and DTS17/00089) and CIBERONC (CD16/12/00442), and co-funded by FEDER from Regional Development European Funds (European Union). A.C. was funded by grants from the Spanish Ministry of Economy and Competitiveness Plan Estatal de I+D+I 2018 cofunded by FEDER: RTI2018-097455-B-I00, CIBER de Cancer (CB16/ 12/00275), co-funded by FEDER from Regional Development European Funds. S.M.P. is funded by the Mutua Madrilena Foundation ~ (2014) Ministry of Health and Social Welfare of Junta de Andalucía (PI-0046-2012, Nicolas Monardes Program C-0040-2016), ISCIII (PI17/00033), and co-funded by FEDER from Regional Development European Funds (European Union). I.F. is funded by the AECC scientific foundation (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and ISCIII (PI16/ 01311) and co-funded by FEDER from Regional Development European Funds (European Union). A.Q. is funded by ISCIII (FI12/00429). L. O. is funded by the Spanish Ministry of Education, Culture and Sport (FPU13/02595). S.V. is supported by the Spanish Ministry of Economy and Competitiveness (MINECO, SAF2017-89944-R)., Comunidad de Madrid, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Fundación Mutua Madrileña, Junta de Andalucía, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Educación, Cultura y Deporte (España), European Regional Development Fund, Regional Government of Andalusia (España), Asociación Española Contra el Cáncer, European Regional Development Fund (ERDF/FEDER), Fundación Mutua Madrileña Automovilista, Gobierno de Andalucia, and Asociacion Espanola Contra el Cancer (AECC)

Subjects
0301 basic medicine, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Lung Neoplasms, Research paper, medicine.medical_treatment, lcsh:Medicine, medicine.disease_cause, Piperazines, Targeted therapy, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Lung neoplasms, Carcinoma, Non-Small-Cell Lung, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [Medical Subject Headings], Tumor Cells, Cultured, Organisms::Eukaryota::Animals [Medical Subject Headings], FGFR inhibitors, Receptor tipo 1 de factor de crecimiento de fibroblastos, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, Fibroblast Growth Factor, Type 1 [Medical Subject Headings], lcsh:R5-920, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [Medical Subject Headings], Receptor tipo 4 de factor de crecimiento de fibroblastos, Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured [Medical Subject Headings], General Medicine, Cadherins, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, Fibroblast Growth Factor, Type 4 [Medical Subject Headings], Predictive biomarker, Fibroblast growth factor receptor, 030220 oncology & carcinogenesis, Benzamides, Female, lcsh:Medicine (General), Neoplasias pulmonares, Mice, Nude, Antineoplastic Agents, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings], General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, In vivo, Cell Line, Tumor, Biomarkers, Tumor, medicine, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], Animals, Humans, Receptor, Fibroblast Growth Factor, Type 4, Receptor, Fibroblast Growth Factor, Type 1, Lung cancer, N-cadherin, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], business.industry, Fibroblast growth factor receptor 1, lcsh:R, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Nude [Medical Subject Headings], Fibroblast growth factor receptor 4, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Cell Adhesion Molecules::Cadherins [Medical Subject Headings], medicine.disease, Isogenic human disease models, stomatognathic diseases, 030104 developmental biology, Biomarcadores, FGFR1, Check Tags::Female [Medical Subject Headings], Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azoles::Pyrazoles [Medical Subject Headings], Drug Resistance, Neoplasm, Cancer research, FGFR4, Pyrazoles, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Piperazines [Medical Subject Headings], Carcinogenesis, business, Chemicals and Drugs::Organic Chemicals::Amides::Benzamides [Medical Subject Headings], Biomarkers, Cadherinas
Abstract

[Background] Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success., [Methods] In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study., [Findings] We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression., [Interpretation] Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy., This work was funded by the Community of Madrid, the ISCIII co-funded by FEDER from Regional Development European Funds (European Union), the Spanish Ministry of Economy and Competitiveness, the Mutua Madrileña Foundation, the Ministry of Health and Social Welfare of Junta de Andalucía, the AECC scientific foundation and the Spanish Ministry of Education, Culture and Sport.

Published
2020

2. Cellular Senescence: Defining a Path Forward

Author

John M. Sedivy, Paul D. Robbins, Cleo L. Bishop, Vassilis G. Gorgoulis, Konstantinos Vougas, Konstantinos Evangelou, Valery Krizhanovsky, Dorothy C. Bennett, Eiji Hara, Diana Jurk, Gerardo Ferbeyre, Judith Campisi, Masashi Narita, Laura J. Niedernhofer, Manuel Serrano, Clemens A. Schmitt, Peter D. Adams, Oliver Bischof, Andrea Alimonti, Marco Demaria, Jesús Gil, Daohong Zhou, Manuel Collado, Thomas von Zglinicki, Andrea B. Maier, João F. Passos, Institut Pasteur [Paris], National and Kapodistrian University of Athens (NKUA), University of Manchester [Manchester], Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), University of Glasgow, Sanford Burnham Prebys Medical Discovery Institute, Oncology Institute of Southern Switzerland (IOSI), Università della Svizzera italiana = University of Italian Switzerland (USI), Universita degli Studi di Padova, Veneto Institute of Molecular Medicine [Padova, Italy] (VIMM), University of London [London], Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bart's and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Buck Institute for Research on Aging, Universidade de Santiago de Compostela [Spain] (USC ), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Université de Montréal (UdeM), MRC London Institute of Medical Sciences (LMC), Imperial College London, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Department of Molecular Cell Biology [Rehovot], Weizmann Institute of Science [Rehovot, Israël], Robert and Arlene Kogod Center on Aging [Rochester, MN, USA], Mayo Clinic, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Melbourne, University of Cambridge [UK] (CAM), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Kepler University Hospital, Brown University, Newcastle University [Newcastle], University of Florida [Gainesville] (UF), Institute for Research in Biomedicine [Barcelona, Spain] (IRB), University of Barcelona-Barcelona Institute of Science and Technology (BIST), Institució Catalana de Recerca i Estudis Avançats (ICREA), University of Groningen [Groningen], European Research Institute for the Biology of Ageing [Groningen] (ERIBA), University Medical Center Groningen [Groningen] (UMCG), M.D. is funded by the Dutch Cancer Foundation, Netherlands (grant ID 10989). V.G., K.E., and K.V. were financially supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grants agreement no. 722729 (SYNTRAIN), the Welfare Foundation for Social & Cultural Sciences (KIKPE), Greece, the KIKPE Foundation, Athens, Greece, Pentagon Biotechnology, UK, DeepMed IO, UK, grant no. 775 from the Hellenic Foundation for Research and Innovation (HFRI), and NKUA-SARG grants 70/3/9816, 70/3/12128, and 70/3/15603. M.S.: is funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and 'laCaixa' Foundation., We would like to thank Nikolaos Kastrinakis, Panagiotis V.S. Vasileiou, Gkikas Magiorkinis, Eleni Fitsiou, and Michela Borghesan for their valuable support to this work. We apologize in advance that, for reason of space, we have omitted the citations of relevant papers and reviews., National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Organisation Nucléaire et Oncogenèse - Nuclear Organization and Oncogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Santiago de Compostela [Spain] (USC), Centre de recherche du Chum [Montréal] (CRCHUM), Université de Montréal [Montréal], Research Institute for Microbial Diseases, Weizmann Institute of Science, University of Minnesota [Twin Cities], Max Delbrück Center for Molecular Medicine [Berlin], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, University of Florida [Gainesville], University of Barcelona, Università degli Studi di Padova = University of Padua (Unipd), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Narita, Masashi [0000-0001-7764-577X], and Apollo - University of Cambridge Repository

Subjects
Senescence, EXPRESSION, Aging, Cell cycle checkpoint, [SDV]Life Sciences [q-bio], Cell, DNA-DAMAGE RESPONSE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Biology, General Biochemistry, Genetics and Molecular Biology, CHROMATIN LANDSCAPE, 03 medical and health sciences, 0302 clinical medicine, MITOCHONDRIA, ONCOGENE-INDUCED SENESCENCE, medicine, Humans, OXIDATIVE STRESS, Senolytic, Cellular Senescence, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, P53, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Genetic Diseases, Inborn, DARK SIDE, Cell Cycle Checkpoints, 06 Biological Sciences, CANCER, Chromatin, medicine.anatomical_structure, Gene Expression Regulation, CELLS, Developmental biology, 030217 neurology & neurosurgery, Biomarkers, Developmental Biology
Abstract

International audience; Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.

Published
2019
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3. Snare-assisted Trans-brachial Stenting for the Cervical Internal Carotid Artery Stenosis of Patient with Aorto-Iliac Occlusion. Technical Case Report.

Author

Oowaki H, Matsuura N, and Ishikawa M

Abstract

Summary: We describe a case of endo-luminal stent placement with Snare-assist for a cervical internal carotid artery stenosis in which percutaneous access was obtained via the brachial artery. A 68-year-old man with known disease of the carotid, peripheral, and coronary arteries, with Human T-cell Lymphotrophic Virus type-1 (HTLV-1) Associated Myelopathy (HAM) presented for endoluminal revascularization of a severe, progressive right internal carotid artery stenosis, but with aorto-iliac occlusion. Transfemoral access was complicated by an aorto-iliac occlusion. A trans-brachial approach was successfully attempted, and a SMARTer stent (Cordis Endovascular, Miami Lakes, FL) was successfully placed through a 7-French Shuttle-SL guide sheath (Cook, Bloomington) under Snare-assist. The trans-brachial approach is becoming an increasingly viable alternative route for stent placement in patients with contra-indicated or complicated femoral access routes. As devices become increasingly more pliable and smaller, the trans-brachial route will be used with increasing frequency in the select patient population for stenting of both the cervical and intracranial circulation.

Published
2006
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