MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma

• Published in: Baillière's best practice & research. Clinical endocrinology & metabolism Vol. 38; no. 6; p. 101931
• Main Authors: Monteagudo, María, Calsina, Bruna, Salazar-Hidalgo, Milton E., Martínez-Montes, Ángel M., Piñeiro-Yáñez, Elena, Caleiras, Eduardo, Martín, Maria Carmen, Rodríguez-Perales, Sandra, Letón, Rocío, Gil, Eduardo, Buffet, Alexandre, Burnichon, Nelly, Fernández-Sanromán, Ángel, Díaz-Talavera, Alberto, Mellid, Sara, Arroba, Ester, Reglero, Clara, Martínez-Puente, Natalia, Roncador, Giovanna, del Olmo, Maria Isabel, Corrales, Pedro José Pinés, Oliveira, Cristina Lamas, Álvarez-Escolá, Cristina, Gutiérrez, María Calatayud, López-Fernández, Adrià, García, Nuria Palacios, Regojo, Rita María, Díaz, Luis Robles, Laorden, Nuria Romero, Guadarrama, Oscar Sanz, Bechmann, Nicole, Beuschlein, Felix, Canu, Letizia, Eisenhofer, Graeme, Fassnacht, Martin, Nölting, Svenja, Quinkler, Marcus, Rapizzi, Elena, Remde, Hanna, Timmers, Henri J., Favier, Judith, Gimenez-Roqueplo, Anne-Paule, Rodriguez-Antona, Cristina, Currás-Freixes, Maria, Al-Shahrour, Fatima, Cascón, Alberto, Leandro-García, Luis J., Montero-Conde, Cristina, Robledo, Mercedes
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.12.2024
• Subjects: Adrenal Gland Neoplasms - genetics; Adrenal Gland Neoplasms - pathology; Adult; DNA-Binding Proteins - genetics; Female; Humans; Male; MAML3 screening procedure; MAML3-fusion; metastasis; Neoplasm Metastasis; paraganglioma; Paraganglioma - genetics; Paraganglioma - pathology; pheochromocytoma; Pheochromocytoma - genetics; Pheochromocytoma - pathology; Trans-Activators - genetics; Transcription Factors - genetics; Tumor Microenvironment - immunology; tumour microenvironment; vasculature; MAML3-fusion; vasculature; metastasis; MAML3 screening procedure; pheochromocytoma; tumour microenvironment; paraganglioma
• ISSN: 1521-690X; 1878-1594
• DOI: 10.1016/j.beem.2024.101931

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.