MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma
Pheochromocytomas 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.
Authors
- Rocío Letón
- Eduardo J. Caleiras (ORCID: https://orcid.org/0000-0001-8768-3630)
- Luis J. Leandro‐García (ORCID: https://orcid.org/0000-0002-7757-2408)
- María Currás-Freixes
- Hanna Remde (ORCID: https://orcid.org/0000-0002-3499-5910)
- Anne‐Paule Gimenez‐Roqueplo (ORCID: https://orcid.org/0000-0002-4816-670X)
- Nuria Palacios García (ORCID: https://orcid.org/0000-0001-7366-2476)
- Giovanna Roncador (ORCID: https://orcid.org/0000-0002-9807-2875)
- Eduardo Gil (ORCID: https://orcid.org/0000-0002-0423-9794)
- Ángel Fernández-Sanromán (ORCID: https://orcid.org/0000-0002-5851-9441)
- Felix Beuschlein (ORCID: https://orcid.org/0000-0001-7826-3984)
- Martin Faßnacht (ORCID: https://orcid.org/0000-0001-6170-6398)
- Cristina Rodríguez‐Antona (ORCID: https://orcid.org/0000-0001-8750-7338)
- María Calatayud Gutiérrez
- Fátima Al‐Shahrour (ORCID: https://orcid.org/0000-0003-2373-769X)
- Adrià López‐Fernández (ORCID: https://orcid.org/0000-0002-2844-5998)
- Judith Favier (ORCID: https://orcid.org/0000-0001-8190-5853)
- Nuria Romero-Laorden (ORCID: https://orcid.org/0000-0001-8715-8860)
- Sara Mellid (ORCID: https://orcid.org/0000-0003-3637-3039)
- Clara Reglero (ORCID: https://orcid.org/0000-0002-3232-5163)
- Graeme Eisenhofer (ORCID: https://orcid.org/0000-0002-8601-9903)
- Henri Timmers (ORCID: https://orcid.org/0000-0002-1208-5748)
- Nicole Bechmann (ORCID: https://orcid.org/0000-0002-6932-333X)
- Bruna Calsina (ORCID: https://orcid.org/0000-0002-6922-9415)
- Rita María Regojo (ORCID: https://orcid.org/0000-0001-9421-1455)
- Elena Piñeiro-Yáñez (ORCID: https://orcid.org/0000-0003-2773-2343)
- Cristina Álvarez‐Escolá (ORCID: https://orcid.org/0000-0002-4684-1652)
- Cristina Lamas (ORCID: https://orcid.org/0000-0003-4622-9508)
- María Isabel Del Olmo-García (ORCID: https://orcid.org/0000-0002-4278-2624)
- Letizia Canu (ORCID: https://orcid.org/0000-0003-4995-8108)
- María Monteagudo (ORCID: https://orcid.org/0000-0002-6280-2987)
- Mercedes Robledo (ORCID: https://orcid.org/0000-0001-6256-5902)
- Sandra Rodríguez (ORCID: https://orcid.org/0000-0001-7221-3636)
- Óscar Sanz Guadarrama
- Natalia Martínez‐Puente (ORCID: https://orcid.org/0000-0002-1521-4111)
- Alberto Díaz‐Talavera (ORCID: https://orcid.org/0000-0003-4279-338X)
- Nelly Burnichon (ORCID: https://orcid.org/0000-0001-7972-5845)
- Svenja Nölting (ORCID: https://orcid.org/0000-0002-7064-590X)
- Alexandre Buffet (ORCID: https://orcid.org/0000-0002-4742-2708)
- Cristina Montero‐Conde (ORCID: https://orcid.org/0000-0002-4452-4469)
- Marcus Quinkler (ORCID: https://orcid.org/0000-0003-4028-1671)
- Alberto Cascón (ORCID: https://orcid.org/0000-0003-2119-891X)
- Elena Rapizzi (ORCID: https://orcid.org/0000-0002-3826-2714)
- Milton E. Salazar-Hidalgo
- Ester Arroba
- Pedro José Pinés Corrales
- Luis Robles Díaz
- Maria Carmen Martín
- Ángel M. Martínez‐Montes (ORCID: https://orcid.org/0000-0003-1461-4516)
Institutions
- Radboud University Nijmegen (NL)
- Inserm (FR)
- Université Paris Cité (FR)
- Instituto Cajal (ES)
- University of Würzburg (DE)
- Hospital Universitario La Paz (ES)
- Radboud University Medical Center (NL)
- LMU Klinikum (DE)
- Hospital Universitari i Politècnic La Fe (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Spanish National Cancer Research Centre (ES)
- Assistance Publique – Hôpitaux de Paris (FR)
- Comprehensive Cancer Center Mainfranken (DE)
- Hôpital Européen Georges-Pompidou (FR)
- Hospital Universitario Puerta de Hierro Majadahonda (ES)
- Hôpital Européen (FR)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Universitätsklinikum Würzburg (DE)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Universitario de La Princesa (ES)
- Paris Cardiovascular Research Center (FR)
- Servicio de Salud de Castilla La Mancha (ES)
- Hospital General Universitario de Albacete (ES)
- Universitätsklinik für Diabetologie, Endokrinologie, Ernährungsmedizin & Metabolismus (CH)
- Hospital Universitario de León (ES)
- University Hospital Carl Gustav Carus (DE)
- University of Florence (IT)
- Universidad Autónoma de Madrid (ES)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- Best Practice & Research Clinical Endocrinology & Metabolism
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1016/j.beem.2024.101931
- Citations
- 8
- Primary Topic
- Adrenal and Paraganglionic Tumors
- Type
- article
- Field-Weighted Citation Impact
- 4.58
Funders
- Instituto de Salud Carlos III
- European Regional Development Fund