Monteagudo, MaríaCalsina, BrunaSalazar-Hidalgo, Milton EMartínez-Montes, Ángel MPiñeiro-Yáñez, ElenaCaleiras, EduardoMartín, Maria CarmenRodríguez-Perales, SandraLetón, RocíoGil, EduardoBuffet, AlexandreBurnichon, NellyFernández-Sanromán, ÁngelDíaz-Talavera, AlbertoMellid, SaraArroba, EsterReglero, ClaraMartínez-Puente, NataliaRoncador, GiovannaDel Olmo, Maria IsabelCorrales, Pedro José PinésOliveira, Cristina LamasÁlvarez-Escolá, CristinaGutiérrez, María CalatayudLópez-Fernández, AdriàGarcía, Nuria PalaciosRegojo, Rita MaríaDíaz, Luis RoblesLaorden, Nuria RomeroGuadarrama, Oscar SanzBechmann, NicoleBeuschlein, FelixCanu, LetiziaEisenhofer, GraemeFassnacht, MartinNölting, SvenjaQuinkler, MarcusRapizzi, ElenaRemde, HannaTimmers, Henri JFavier, JudithGimenez-Roqueplo, Anne-PauleRodriguez-Antona, CristinaCurrás-Freixes, MariaAl-Shahrour, FatimaCascón, AlbertoLeandro-García, Luis JMontero-Conde, CristinaRobledo Batanero, Mercedes2025-01-132025-01-132024-12Best Pract Res Clin Endocrinol Metab . 2024 Dec;38(6):101931.https://hdl.handle.net/20.500.12105/26006Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.This work was supported by Project PI17/01796 and PI20/01169 to M.R. [Instituto de Salud Carlos III (ISCIII) , Accion Estrategica en Salud, cofinanciado a traves del Fondo Europeo de Desarrollo Regional (FEDER) ] , Paradifference Foundation [no grant number applicable to M.R.] , Pheipas Association [no grant number applicable to M.R.] , Spanish National Research and Development Plan, Instituto de Salud Carlos III, and FEDER (PI20/01837 to S.R-P) , and Asociacion Espanola Contra el Cancer (AECC-LABAE20049RODR to S.R-P.) . M.E.S.H is supported by ISCIII (Project: IMPaCT_VUSCan, Ref. PMP22/00064) A.M.M.M. was supported by CAM (S2017/BMD-3724; and Paradifference Foundation) , M.M. and S.M. are supported bythe Spanish Ministry of Science, Innovation and Universities "Formacion del Profesorado Universitario- FPU" fellowship with ID number FPU18/00064, and FPU19/04940. E.A. is supported by CAM (P2022/BMD-7379, iTIRONET-CM) . C.R. is supported by the CNIO Friends Postdoctoral Contract Program. A.D.T. is supported by the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) . L.J.L.G. was supported by La Caixa Postdoctoral Junior Leader Fellowship (LCF/BQ/PI20/11760011) . A.F.S. received the support of a fellowship from La Caixa Foundation (ID 100010434; LCF/BQ/DR21/11880009) . C.M.C. was supported by a grant from the AECC Foundation (AIO15152858 MONT) . F.B. and S.N. were supported as part of an Immuno-TargET project under the umbrella of University Medicine Zurich. N.B. and G.E. were financially supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the CRC/Transregio 205/1, Project No. 314061271-TRR205 "The Adrenal: Central Relay in Health and Disease".r the Spanish Ministry of Science, Innovation and Universities "Formacion del Profesorado Universitario- FPU" fellowship with ID number FPU18/00064, and FPU19/04940. E.A. is supported by CAM (P2022/BMD-7379, iTIRONET-CM) . C.R. is supported by the CNIO Friends Postdoctoral Contract Program. A.D.T. is supported by the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) . L.J.L.G. was supported by La Caixa Postdoctoral Junior Leader Fellowship (LCF/BQ/PI20/11760011) . A.F.S. received the support of a fellowship from La Caixa Foundation (ID 100010434; LCF/BQ/DR21/118800 09) . C.M.C. was supported by a grant from the AECC Foundation (AIO15152858 MONT) . F.B. and S.N. were supported as part of an Immuno-TargET project under the umbrella of University Medicine Zurich. N.B. and G.E. were financially supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the CRC/Transregio 205/1, Project No. 314061271-TRR205 "The Adrenal: Central Relay in Health and Disease".engVoRMAML3 screening procedureMAML3-fusionmetastasisparagangliomapheochromocytomatumour microenvironmentvasculature39218714386101931Best Pract Res Clin Endocrinol Metabopen access