MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma
Year: 2024
Type: article
Study design: Observational Study
Abstract: 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: María Monteagudo, Bruna Calsina, Milton E. Salazar-Hidalgo, Ángel M. Martínez-Montes, Elena Piñeiro-Yáñez, Eduardo Caleiras, Maria Carmen Martín, Sandra Rodríguez-Perales, Rocío Letón, Eduardo Gil, Alexandre Buffet, Nelly Burnichon, Ángel Fernández-Sanromán, Alberto Díaz-Talavera, Sara Mellid, Ester Arroba, Clara Reglero, Natalia Martínez-Puente, Giovanna Roncador, Maria Isabel del Olmo, Pedro José Pinés Corrales, Cristina Lamas Oliveira, Cristina Álvarez-Escolá, María Calatayud Gutiérrez, Adrià López-Fernández, Nuria Palacios García, Rita María Regojo, Luis Robles Díaz, Nuria Romero Laorden, Oscar Sanz Guadarrama, Nicole Bechmann, Felix Beuschlein, Letizia Canu, Graeme Eisenhofer, Martin Fassnacht, Svenja Nölting, Marcus Quinkler, Elena Rapizzi, Hanna Remde, Henri J. Timmers, Judith Favier, Anne-Paule Gimenez-Roqueplo, Cristina Rodriguez-Antona, Maria Currás-Freixes, Fatima Al-Shahrour, Alberto Cascón, Luis J. Leandro-García, Cristina Montero-Conde, Mercedes Robledo
Institutions: Instituto Cajal, Spanish National Cancer Research Centre, Universidad Autónoma de Madrid, Inserm, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris Cardiovascular Research Center, Centre for Biomedical Network Research on Rare Diseases, Hospital Universitari i Politècnic La Fe, Servicio de Salud de Castilla La Mancha, Hospital General Universitario de Albacete, Complejo Hospitalario Universitario de Albacete, Hospital Universitario La Paz, Hospital Universitario 12 De Octubre, Vall d'Hebron Hospital Universitari, Radboud University Nijmegen, Radboud University Medical Center, Hospital Universitario Puerta de Hierro Majadahonda, Hospital Universitario de La Princesa, Hospital Universitario de León, University Hospital Carl Gustav Carus, Technische Universität Dresden, LMU Klinikum, University Hospital Zurich, Ludwig-Maximilians-Universität München, University of Florence, University of Würzburg, Comprehensive Cancer Center Mainfranken, Universitätsklinikum Würzburg
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,150
Funders: Ministerio de Ciencia, Innovación y Universidades, ACCP Foundation, Paradifference foundation, Deutsche Forschungsgemeinschaft, Fundación Científica Asociación Española Contra el Cáncer, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Instituto de Salud Carlos III, European Regional Development Fund, Hochschulmedizin Zürich
Awards: G1991778758, TRR 205: Die Nebenniere: Zentrales Relais in Gesundheit und Krankheit, Mecanismos asociados a progresión de tumores endocrinos y neuroendocrinos, G6890145747, Uso del sistema CRISPR/Cas13 para el diagnóstico e inhibición de oncogenes de fusión, Caracterización de nuevas alteraciones moleculares asociadas a desarrollo y progresión de tumores raros endocrinos y neuroendocrinos. Marcadores predictivos de sensibilidad a tratamiento., Genómica funcional: desarrollo e implementación de una plataforma para el estudio de casos de cáncer hereditario sin resolver, G7685134749, G8421502675, G875776022, G8768840204
OpenAlex ID: W4402024180