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Murakami, M.* ; Sun, N. ; Greunke, C. ; Feuchtinger, A. ; Kircher, S.* ; Deutschbein, T.* ; Papathomas, T.* ; Bechmann, N.* ; Wallace, P.W.* ; Peitzsch, M.* ; Korpershoek, E.* ; Friemel, J.* ; Gimenez Roqueplo, A.P.* ; Robledo, M.* ; Timmers, H.J.* ; Canu, L.* ; Weber, A.* ; de Krijger, R.R.* ; Fassnacht, M.* ; Knösel, T.* ; Kirchner, T.* ; Reincke, M.* ; Walch, A.K. ; Kroiss, M.* ; Beuschlein, F.*

Mass spectrometry imaging identifies metabolic patterns associated with malignant potential in pheochromocytoma and paraganglioma.

Eur. J. Endocrinol. 185, 179-191 (2021)
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Open Access Green as soon as Postprint is submitted to ZB.
OBJECTIVE: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translate these alterations into functional autonomy and potentially malignant behavior have 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. DESIGN AND METHODS: 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 in vitro. RESULTS: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 5.06E-11) 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 P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knock-down of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. CONCLUSIONS: 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Germline Mutations; Kynurenic Acid; Expression; Predisposition; Confer
ISSN (print) / ISBN 0804-4643
e-ISSN 1479-683X
Quellenangaben Volume: 185, Issue: 1, Pages: 179-191 Article Number: , Supplement: ,
Publisher BioScientifica
Publishing Place Starling House, 1600 Bristol Parkway N, Bristol, England
Reviewing status Peer reviewed
Grants Uehara Memorial Foundation
German Cancer Aid
Clinical Research Priority Program of the University of Zurich
Instituto de Salud Carlos III (ISCIII)
Accion Estrategica en Salud
Paradifference Foundation
Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad
German Research Foundation (DFG)