2. Academic Validation
  3. Epigenetic and metabolic rewiring in metastatic pheochromocytomas and paragangliomas driven by SDHB mutations

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

  • Commun Biol. 2026 Jan 15;9(1):266. doi: 10.1038/s42003-026-09543-9.
Tamara Cubiella # 1 2,  Juan José Alba-Linares # 1 2 3 4,  Jaime San-Juan-Guardado 1 2,  Alvaro Suarez-Priede 1 2,  Nerea Gómez-Suárez 1 2,  Maria Tous 5,  Irina Bancos 6,  Carles Villabona 7,  Teresa Serrano 8,  Isabel Tena 9,  Maribel Del Olmo 10,  Lluis Forga 11,  Nuria Valdés 12,  Mario F Fraga 1 2 3 4 13,  María-Dolores Chiara 14 15
Affiliations

Affiliations

  • 1 Institute of Oncology of Principality of Asturias, Universidad de Oviedo, Oviedo, Spain.
  • 2 Health Research Institute of Principality of Asturias, Oviedo, Spain.
  • 3 Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center-Spanish National Research Council (CINN-CSIC), Universidad de Oviedo, Oviedo, Spain.
  • 4 Biomedical Research Networking Center on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.
  • 5 Unidad de Gestión Clínica of Endocrinology and Nutrition, Hospital Virgen Macarena, Seville, Spain.
  • 6 Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.
  • 7 Service of Endocrinology and Nutrition, Hospital Universitario de Bellvitge, Barcelona, Spain.
  • 8 Service of Pathology, Hospital Universitario de Bellvitge, Barcelona, Spain.
  • 9 Service of Medical Oncology, Hospital Provincial de Castellón, Castellón, Spain.
  • 10 Service of Endocrinology and Nutrition, Hospital Universitario La Fe, Valencia, Spain.
  • 11 Service of Endocrinology and Nutrition, Complejo Universitario de Navarra, Pamplona, Spain.
  • 12 Endocrinology and Nutrition Department, Hospital Universitario Cruces, Biobizkaia, UPV/EHU, CIBERDEM, CIBERER, Endo-ERN, Barakaldo, Bizkaia, Spain.
  • 13 Department of Organisms and Systems Biology (B.O.S.), Universidad of Oviedo, Oviedo, Spain.
  • 14 Institute of Oncology of Principality of Asturias, Universidad de Oviedo, Oviedo, Spain. [email protected].
  • 15 Health Research Institute of Principality of Asturias, Oviedo, Spain. [email protected].
  • # Contributed equally.
PMID: 41540233 DOI: 10.1038/s42003-026-09543-9
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.

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