{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:49:17Z","timestamp":1790254157754,"version":"4.1.0"},"reference-count":0,"publisher":"Bioscientifica","issue":"11","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:p>\n                    Mutations that drive the stabilization of hypoxia inducible factor 2\u03b1 (HIF2\u03b1) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2\u03b1 in predisposition to metastatic disease remains unclear. To assess such a role we combined gene-manipulations in pheochromocytoma cell lines with retrospective analyses of patient data and gene expression profiling in tumor specimens. Among 425 patients with PPGLs identified with mutations in tumor-susceptibility genes, those with tumors due to activation of pseudohypoxic pathways had a higher frequency of metastatic disease than those with tumors due to activation of kinase-signaling pathways, even without inclusion of patients with mutations in\n                    <jats:italic>SDHB<\/jats:italic>\n                    (18.6% vs 4.3% in,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001). Three out of nine (33%) patients with gain-of-function mutations in\n                    <jats:italic>HIF2\u03b1<\/jats:italic>\n                    had metastatic disease. In cell line studies, elevated expression of\n                    <jats:italic>HIF2\u03b1<\/jats:italic>\n                    enhanced cell proliferation and led to increased migration and invasion capacity. Moreover,\n                    <jats:italic>HIF2\u03b1<\/jats:italic>\n                    expression in HIF2\u03b1-deficient cells resulted in increased cell motility, diffuse cluster formation and emergence of pseudopodia indicating changes in cell adhesion and cytoskeletal remodeling. In a mouse liver metastasis model,\n                    <jats:italic>Hif2a<\/jats:italic>\n                    enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix\u2013receptor interactions in\n                    <jats:italic>HIF2\u03b1<\/jats:italic>\n                    -mutated PPGLs. Our translational findings demonstrate that HIF2\u03b1 supports pro-metastatic behavior in PPGLs, though other factors remain critical for subsequent transition to metastasis. We identified\n                    <jats:italic>LAMB1<\/jats:italic>\n                    and\n                    <jats:italic>COL4A2<\/jats:italic>\n                    as new potential therapeutic targets for HIF2\u03b1-driven PPGLs. Identified HIF2\u03b1 downstream targets might open a new therapeutic window for aggressive HIF2\u03b1-expressing tumors.\n                  <\/jats:p>","DOI":"10.1530\/erc-20-0205","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T07:19:56Z","timestamp":1600067996000},"page":"625-640","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":50,"title":["HIF2\u03b1 supports pro-metastatic behavior in pheochromocytomas\/paragangliomas"],"prefix":"10.1530","volume":"27","author":[{"given":"Nicole","family":"Bechmann","sequence":"first","affiliation":[{"name":"1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"},{"name":"2Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"},{"name":"3Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany"},{"name":"4German Center for Diabetes Research (DZD), M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats Leif","family":"Moskopp","sequence":"additional","affiliation":[{"name":"5Department of Neurosurgery, Vivantes Friedrichshain Hospital, Charit\u00e9 Academic Teaching Hospital, Landsberger Allee, Berlin, Germany"},{"name":"6Institute of Physiology, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ullrich","sequence":"additional","affiliation":[{"name":"7Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Calsina","sequence":"additional","affiliation":[{"name":"8Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain"},{"name":"9Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e5l William","family":"Wallace","sequence":"additional","affiliation":[{"name":"1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Richter","sequence":"additional","affiliation":[{"name":"1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Friedemann","sequence":"additional","affiliation":[{"name":"1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Langton","sequence":"additional","affiliation":[{"name":"2Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M J","family":"Fliedner","sequence":"additional","affiliation":[{"name":"10First Department of Medicine, University Medical Center Schleswig-Holstein, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri J L M","family":"Timmers","sequence":"additional","affiliation":[{"name":"11Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"N\u00f6lting","sequence":"additional","affiliation":[{"name":"12Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Beuschlein","sequence":"additional","affiliation":[{"name":"12Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany"},{"name":"13Department of Endocrinology, Diabetology and Clinical Nutrition, Univiersit\u00e4tsSpital Z\u00fcrich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Fassnacht","sequence":"additional","affiliation":[{"name":"14Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Prejbisz","sequence":"additional","affiliation":[{"name":"15Department of Hypertension, National Institute of Cardiology, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Pacak","sequence":"additional","affiliation":[{"name":"16Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans K","family":"Ghayee","sequence":"additional","affiliation":[{"name":"17Department of Medicine, Division of Endocrinology, University of Florida College of Medicine and Malcom Randall VA Medical Center, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan R","family":"Bornstein","sequence":"additional","affiliation":[{"name":"2Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dieterich","sequence":"additional","affiliation":[{"name":"6Institute of Physiology, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"7Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse, Dresden, Germany"},{"name":"18Faculty of Chemistry and Food Chemistry, School of Science, Technische Universit\u00e4t Dresden, Mommsenstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Wielockx","sequence":"additional","affiliation":[{"name":"1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"8Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain"},{"name":"9Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Qin","sequence":"additional","affiliation":[{"name":"19Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"name":"20German Consortium for Translational Cancer Research (DKTK), partner site Essen\/D\u00fcsseldorf, D\u00fcsseldorf, Germany"},{"name":"21Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital D\u00fcsseldorf, D\u00fcsseldorf, Germany"},{"name":"22Department of Neuropathology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Eisenhofer","sequence":"additional","affiliation":[{"name":"1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"},{"name":"2Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Fetscherstrasse, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Endocrine-Related 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