Epigenetic and metabolic rewiring in metastatic pheochromocytomas and paragangliomas driven by SDHB mutations.

Pheochromocytomas and paragangliomas (PPGLs) with SDHB mutations frequently develop metastases, but the molecular mechanisms driving this progression remain unclear. Here we show that SDHB-mutant metastatic PPGLs display an amplified hypermethylation signature, particularly in genes involved in neuronal differentiation, building on previous findings in SDHx-mutated tumors. This epigenetic shift is already detectable in benign SDHB-mutant tumors, suggesting early priming toward a less differentiated state. In parallel, we identify hypomethylation of genes linked to carbohydrate metabolism, notably the fructose transporter SLC2A5. Functional assays reveal that SDHB loss, hypoxia, exogenous succinate, and fructose availability promote tumor cell growth and induce cell-type-restricted, SDHB-dependent, induction of SLC2A5 expression. These findings highlight the dual role of SDHB mutations in driving epigenetic reprogramming and metabolic adaptation, promoting tumor cell plasticity and survival under metabolic stress. By uncovering a fructose-driven metabolic vulnerability, our study provides insights into the molecular mechanisms underlying metastatic PPGLs and identifies potential therapeutic targets at the intersection of epigenetic and metabolic regulation.