HIF2 alpha supports pro-metastatic behavior in pheochromocytomas/paragangliomas

Bechmann, Nicole; Moskopp, Mats Leif; Ullrich, Martin; Calsina, Bruna; Wallace, Pal William; Richter, Susan; Friedemann, Markus; Langton, Katharina; Fliedner, Stephanie M. J.; Timmers, Henri J. L. M.; Noelting, Svenja; Beuschlein, Felix; Fassnacht, Martin; Prejbisz, Aleksander; Pacak, Karel; Ghayee, Hans K.; Bornstein, Stefan R.; Dieterich, Peter; Pietzsch, Jens; Wielockx, Ben; Robledo, Mercedes; Qin, Nan und Eisenhofer, Graeme (2020): HIF2 alpha supports pro-metastatic behavior in pheochromocytomas/paragangliomas. In: Endocrine-Related Cancer, Bd. 27, Nr. 11: S. 625-640

Abstract

Mutations that drive the stabilization of hypoxia inducible factor 2 alpha (HIF2 alpha) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2 alpha 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 HIF2 alpha had metastatic disease. In cell line studies, elevated expression of HIF2a enhanced cell proliferation and led to increased migration and invasion capacity. Moreover, HIF2 alpha expression in HIF2 alpha-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, Hif2 alpha enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix-receptor interactions in HIF2 alpha-mutated PPGLs. Our translational findings demonstrate that HIF2 alpha 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 HIF2 alpha-driven PPGLs. Identified HIF2 alpha downstream targets might open a new therapeutic window for aggressive HIF2 alpha-expressing tumors.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1351-0088
• Sprache: Englisch