Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Cubiella T

PROVIDER: S-EPMC12913883 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature

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

Cubiella Tamara T Alba-Linares Juan José JJ San-Juan-Guardado Jaime J Suarez-Priede Alvaro A Gómez-Suárez Nerea N Tous Maria M Bancos Irina I Villabona Carles C Serrano Teresa T Tena Isabel I Del Olmo Maribel M Forga Lluis L Valdés Nuria N Fraga Mario F MF Chiara María-Dolores MD

Communications biology 20260115 1

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 differentia ...[more]

PMID: 41540233

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Project description:Introduction: Genotype constitutes a pivotal factor in the comprehensive management of pheochromocytomas and paragangliomas (PPGLs). This underlines the need to (1) further elucidate the genetic etiology of these pathologies, (2) investigate the underlying pathogenic mechanisms, and (3) identify therapeutic targets. These goals rely on generating and studying relevant biological models, particularly in vivo. However, this has remained a disappointment using traditional animal models. In this context, there is a need to develop fast, reliable in vivo models of PPGLs which display clinically relevant biochemical hallmarks of PPGLs. Objective: Our study aims to establish zebrafish larvae as a relevant and convenient proxy for the functional characterization of PPGL-associated genetic variants. Methods: We took advantage of the genetic accessibility of zebrafish embryos to generate first-generation (F0) loss-of-function models for sdhb, a canonical PPGL-associated gene, using CRISPR/CAS9 technology. F0 zebrafish embryos were microinjected with a CRISPR/CAS9 molecular cocktail containing sdhb-specific guide RNAs and compared with control embryos injected with non-active CRISPR/CAS9. The mutagenic score of our CRISPR/CAS9 approach was validated by High-Resolution Melting analysis, and mutant zebrafish larvae were phenotyped during their first five days of development. Notably, the levels of catecholamines/metanephrines (in whole fish extract and bathing medium) and Krebs cycle metabolites were assessed by liquid chromatography-mass spectrometry. Other relevant phenotypic readouts were also performed, such as heart rate, swimming activity and overall survival. To validate the specificity of our findings, we also analyzed other zebrafish genetic mutants diseased controls (i.e. nf1 CRISPants as PPGL positive controls and scn1a-mutant as non-PPGL negative genetic controls). Finally, we performed an RNA-sequencing assay from sdhb-CRISPant and controls larvae. Results: Sdhb CRISPants exhibit increased heart rates, reduced swimming activity and premature death. In whole fish extracts, normetanephrine (NM), metanephrine (MN), and dopamine (DA) levels were about three times higher in sdhb CRISPants than in control larvae. In the bathing medium, NM and MN were also significantly elevated, along with 3-MT. We confirmed the specificity of our findings by showing that nf1-mutant larvae exhibit similar catecholamine levels but also show an adrenergic phenotype typical of cluster 2 variants of PPGLs. In contrast, scn1a-mutant larvae, despite suffering from severe epileptic encephalopathy associated with reduced lifespan, did not display elevated catecholamine levels. Complementary metabolic profiling showed that sdhb CRISPants depict a clear Complex II dysfunction signature, characterized by elevated succinate, lactate, NAD+, along with reduced aspartate and glutamate levels. Additionally, RNA-sequencing revealed downregulation of sdhb and fads2, and upregulation of genes involved in the hypoxia response, angiogenesis, stress response, and glycolysis in sdhb CRISPants compared to Cas9-control larvae. Conclusion: In this work, we validated the relevance of F0 loss-of-function zebrafish models (CRISPant) to study the pathogenicity of PPGL-causing genetic variants in vivo. We present the first in vivo model of sdhb loss-of-function with oversecretion of free catecholamines, a key clinical hallmark of PPGLs in humans. We also show that other pathological molecular hallmarks are found increased such as Krebs cycle metabolites and relevant phenotypic readouts (tachycardia, reduced lifespan, and consistent transcriptomic dysregulations). These findings suggest that zebrafish is a relevant physiopathologic model for studying PPGLs and their associated genetic etiologies and opens the door for streamlining preclinical precision medicine approaches for PPGLs.

Dataset Information

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

Publications

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

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