Clinical implications of splicing machinery alteration in Pheochromocytomas and Paragangliomas

Moreno Montilla Maria Trinidad; Vioque Victor Garcia; Encinas Rey Ricardo Blazquez; Martinez Montes Angel Mario; Emilia Alors-Perez; Federica Mangili; Sergio Pedraza-Arevalo; Mercedes Robledo; Justo P. Castano; Costa Alejandro Ibanez

doi:10.1530/endoabs.90.P109

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Endocrine Abstracts (2023) 90 P109 | DOI: 10.1530/endoabs.90.P109

ECE2023 Poster Presentations Endocrine-related Cancer (62 abstracts)

Clinical implications of splicing machinery alteration in Pheochromocytomas and Paragangliomas

María Trinidad Moreno Montilla ^1,2,3 , Víctor García Vioque ^1,2,3 , Ricardo Blázquez Encinas Rey ^1,2,3 , Angel Mario Martinez Montes ⁴ , Emilia Alors-Pérez ^1,2,3 , Federica Mangili ^1,2,3,5 , Sergio Pedraza-Arevalo ^1,2,3 , Mercedes Robledo ^4,6 , Justo P. Castaño ^1,2,3,7 & Alejandro Ibañez Costa ^1,2,3

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¹Maimonides Biomedical Research Institute of Cordoba, Cordoba, Spain; ²Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain; ³Reina Sofia University Hospital, Cordoba, Spain; ⁴Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; ⁵Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; ⁶Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Madrid, Spain; ⁷CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain

Pheochromocytomas and paragangliomas (PPGL) are infrequent neuroendocrine neoplasms, which develop metastases or aggressive behaviour in 25 % patients. They can be classified into three clusters according to their molecular features; nevertheless, these differences may not stratify patients according to their prognosis. The dysregulation of the splicing process has emerged as a novel feature shared by most cancers, which is associated with an aggressive phenotype in several tumours, including NETs, but it has not been explored in PPGL. The purpose of this study was to determine the splicing machinery profile in PPGL, its relationship with clinical/molecular features, and to investigate the functional role of splicing inhibitors in vitro. We investigated the expression of 310 splicing-related genes in a dataset of 196 PPGL and analysed their relationship with clinical features of patients and tumor phenotypes, which was validated using the TCGA dataset. SK-N-AS (WT and SDHB knock-down), and PC12 cell lines were used to perform in vitro assays testing the effects of the SF3B1 inhibitor Pladienolide B. Pheochromocytomas and paragangliomas show clearly distinct profiles of splicing machinery components. Interestingly, clear differences were observed among the molecular clusters. Furthermore, the expression levels of certain splicing-related genes were associated to metastasis, aggressiveness, and low survival. The in vitro blockade of the splicing process reduced functional parameters of aggressiveness as proliferation, colony formation, migration, and sphere formation. Finally, our findings revealed that the splicing machinery is severely altered in PPGL, which may be associated with key clinical features, and its modulation may improve tumour aggressiveness.

Keywords: pheochromocytoma, paraganglioma, splicing dysregulation, splicing machinery, pladienolide B.