PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Mohr, H. ; Ballke, S.* ; Bechmann, N.* ; Gulde, S. ; Malekzadeh Najafabadi, J. ; Peitzsch, M.* ; Ntziachristos, V. ; Steiger, K.* ; Wiedemann, T. ; Pellegata, N.S.

Mutation of the cell cycle regulator p27kip1 drives pseudohypoxic pheochromocytoma development.

Cancers 13:126 (2021)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Pseudohypoxic tumors activate pro-oncogenic pathways typically associated with severe hypoxia even when sufficient oxygen is present, leading to highly aggressive tumors. Prime examples are pseudohypoxic pheochromocytomas and paragangliomas (p-PPGLs), neuroendendocrine tumors currently lacking effective therapy. Previous attempts to generate mouse models for p-PPGLs all failed. Here, we describe that the rat MENX line, carrying a Cdkn1b (p27) frameshift-mutation, spontaneously develops pseudohypoxic pheochromocytoma (p-PCC). METHODS: We compared rat p-PCCs with their cognate human tumors at different levels: histology, immunohistochemistry, catecholamine profiling, electron microscopy, transcriptome and metabolome. The vessel architecture and angiogenic potential of pheochromocytomas (PCCs) was analyzed by light-sheet fluorescence microscopy ex vivo and multi-spectral optoacoustic tomography (MSOT) in vivo. RESULTS: The analysis of tissues at various stages, from hyperplasia to advanced grades, allowed us to correlate tumor characteristics with progression. Pathological changes affecting the mitochrondrial ultrastructure where present already in hyperplasias. Rat PCCs secreted high levels of norepinephrine and dopamine. Transcriptomic and metabolomic analysis revealed changes in oxidative phosphorylation that aggravated over time, leading to an accumulation of the oncometabolite 2-hydroxyglutarate, and to hypermethylation, evident by the loss of the epigenetic mark 5-hmC. While rat PCC xenografts showed high oxygenation, induced by massive neoangiogenesis, rat primary PCC transcriptomes possessed a pseudohypoxic signature of high Hif2a, Vegfa, and low Pnmt expression, thereby clustering with human p-PPGL. CONCLUSION: Endogenous rat PCCs recapitulate key phenotypic features of human p-PPGLs. Thus, MENX rats emerge as the best available animal model of these aggressive tumors. Our study provides evidence of a link between cell cycle dysregulation and pseudohypoxia.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
6.639
1.292
4
6
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 2-hydroxyglutarate ; 5-hmc ; Menx ; Ppgls ; Angiogenesis ; Animal Model ; Cell Cycle ; Endogenous Pheochromocytoma ; Hypermethylation ; Mitochondrial Dysfunction ; Oncometabolites ; Pseudohypoxia; Optoacoustic Tomography Msot; Endocrine Neoplasia Syndrome; Malignant Pheochromocytoma; Mitochondrial Cristae; Deficient Cells; Expression; Catecholamines; Inhibition; Therapy; Models
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 2072-6694
Zeitschrift Cancers
Quellenangaben Band: 13, Heft: 1, Seiten: , Artikelnummer: 126 Supplement: ,
Verlag MDPI
Verlagsort St Alban-anlage 66, Ch-4052 Basel, Switzerland
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Biological and Medical Imaging (IBMI)
POF Topic(s) 30201 - Metabolic Health
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP-Element(e) G-502590-001
G-505500-001
Förderungen Deutsche Forschungsgemeinschaft
DOI 10.3390/cancers13010126
WOS ID WOS:000605774500001
Scopus ID 85099969841
PubMed ID 33401758
Erfassungsdatum 2021-03-25
[➜Korrektur melden]