HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas

in Endocrine-Related Cancer
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  • 1 Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany
  • 2 Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany
  • 3 Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 4 German Center for Diabetes Research (DZD), München-Neuherberg, Germany
  • 5 Department of Neurosurgery, Vivantes Friedrichshain Hospital, Charité Academic Teaching Hospital, Landsberger Allee, Berlin, Germany
  • 6 Institute of Physiology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany
  • 7 Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse, Dresden, Germany
  • 8 Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • 9 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  • 10 First Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
  • 11 Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
  • 12 Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
  • 13 Department of Endocrinology, Diabetology and Clinical Nutrition, UniviersitätsSpital Zürich, Zurich, Switzerland
  • 14 Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany
  • 15 Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
  • 16 Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
  • 17 Department of Medicine, Division of Endocrinology, University of Florida College of Medicine and Malcom Randall VA Medical Center, Gainesville, Florida, USA
  • 18 Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstrasse, Dresden, Germany
  • 19 Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 20 German Consortium for Translational Cancer Research (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
  • 21 Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
  • 22 Department of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

Correspondence should be addressed to N Bechmann: nicole.bechmann@uniklinikum-dresden.de
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Mutations that drive the stabilization of hypoxia inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2α 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 SDHB (18.6% vs 4.3% in, P < 0.0001). Three out of nine (33%) patients with gain-of-function mutations in HIF2α had metastatic disease. In cell line studies, elevated expression of HIF2α enhanced cell proliferation and led to increased migration and invasion capacity. Moreover, HIF2α expression in HIF2α-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, Hif2a enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix–receptor interactions in HIF2α-mutated PPGLs. Our translational findings demonstrate that HIF2α supports pro-metastatic behavior in PPGLs, though other factors remain critical for subsequent transition to metastasis. We identified LAMB1 and COL4A2 as new potential therapeutic targets for HIF2α-driven PPGLs. Identified HIF2α downstream targets might open a new therapeutic window for aggressive HIF2α-expressing tumors.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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