{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T16:58:37Z","timestamp":1783961917793,"version":"3.55.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"1","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,7,1]]},"abstract":"<jats:sec>\n<jats:title>Objective<\/jats:title>\n<jats:p>Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Design and methods<\/jats:title>\n<jats:p>MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact <jats:italic>in vitro<\/jats:italic>.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (<jats:italic>P<\/jats:italic>\u2009=\u20092.35E\u221209) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests <jats:italic>P<\/jats:italic>\u2009=\u20097.96E\u221206) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, <jats:italic>P<\/jats:italic>\u2009=\u20090.002). Knockdown of <jats:italic>Sdhb<\/jats:italic> and <jats:italic>Vhl<\/jats:italic> in an <jats:italic>in vitro<\/jats:italic> model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-20-1407","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T15:39:41Z","timestamp":1620920381000},"page":"179-191","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":16,"title":["Mass spectrometry imaging identifies metabolic patterns associated with malignant potential in pheochromocytoma and paraganglioma"],"prefix":"10.1093","volume":"185","author":[{"given":"Masanori","family":"Murakami","sequence":"first","affiliation":[{"name":"1Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Sun","sequence":"additional","affiliation":[{"name":"2Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"},{"name":"1Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Greunke","sequence":"additional","affiliation":[{"name":"2Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Feuchtinger","sequence":"additional","affiliation":[{"name":"2Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kircher","sequence":"additional","affiliation":[{"name":"3Institute for Pathology, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Deutschbein","sequence":"additional","affiliation":[{"name":"4Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital W\u00fcrzburg, University of W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"5Medicover Oldenburg MVZ, Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Papathomas","sequence":"additional","affiliation":[{"name":"7Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Bechmann","sequence":"additional","affiliation":[{"name":"8Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"},{"name":"9Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"},{"name":"10Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany"},{"name":"11German Center for Diabetes Research (DZD), M\u00fcnchen-Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paal","family":"William Wallace","sequence":"additional","affiliation":[{"name":"8Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Peitzsch","sequence":"additional","affiliation":[{"name":"8Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Korpershoek","sequence":"additional","affiliation":[{"name":"12Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Friemel","sequence":"additional","affiliation":[{"name":"13Institute for Pathology and Molecular Pathology, Universit\u00e4tsspital Z\u00fcrich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Paule","family":"Gimenez-Roqueplo","sequence":"additional","affiliation":[{"name":"14Universit\u00e9 de Paris, PARCC, INSERM, Equipe labellis\u00e9e par la Ligue contre le Cancer, Paris, France"},{"name":"15Genetics department, AP-HP, H\u00f4pital europ\u00e9en Georges Pompidou, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"16Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri","family":"J L M Timmers","sequence":"additional","affiliation":[{"name":"17Department of Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Canu","sequence":"additional","affiliation":[{"name":"18Department of Experimental and Clinical Biomedical Sciences \u2018Mario Serio\u2019, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Weber","sequence":"additional","affiliation":[{"name":"13Institute for Pathology and Molecular Pathology, Universit\u00e4tsspital Z\u00fcrich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"R de Krijger","sequence":"additional","affiliation":[{"name":"19Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands"},{"name":"20Princess M\u00e1xima Center for Pediatric Oncology, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Fassnacht","sequence":"additional","affiliation":[{"name":"4Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital W\u00fcrzburg, University of W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"6Comprehensive Cancer Center Mainfranken, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kn\u00f6sel","sequence":"additional","affiliation":[{"name":"21Institute of Pathology, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kirchner","sequence":"additional","affiliation":[{"name":"21Institute of Pathology, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Reincke","sequence":"additional","affiliation":[{"name":"1Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Karl Walch","sequence":"additional","affiliation":[{"name":"2Research Unit Analytical Pathology, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kroiss","sequence":"additional","affiliation":[{"name":"1Medizinische 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