ECE2020 Oral Communications Young Investigators (12 abstracts)
Splicing machinery is dysregulated in craniopharyngiomas: a novel source of diagnostic, prognostic and therapeutic biomarkers
Antonio C Fuentes-Fayos 1,2,3,4 , Teresa Sanchez-Medianero 1,5 , David A Cano 6,7 , Antonio J Martínez-Ortega 6,7 , Álvaro Toledano-Delgado 1,8 , Elena Dios 6,7 , Eva Venegas-Moreno 6,7 , Eugenio Cárdenas 6,9 , Juan P Martínez-Barbera 10 , Justo P Castaño 1,2,3,4 , Alfonso Soto-Moreno 6,7 , Rosa M Ortega Salas 1,5 & Raúl M Luque 1,2,3,4
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; 2University of Cordoba, Department of Cell Biology, Physiology and Immunology, Cordoba, Spain; 3Reina Sofia University Hospital (HURS), Cordoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain; 5Reina Sofia University Hospital (HURS), Anatomical Pathology Service, Cordoba, Spain; 6Instituto de Biomedicina de Sevilla (IBIS), Endocrine Pathologies, Seville, Spain; 7Hospital Universitario Virgen del Rocío, Metabolism and Nutrition Unit, Seville, Spain; 8Reina Sofia University Hospital (HURS), Service of Neurosurgery, Cordoba, Spain; 9Hospital Universitario Virgen del Rocío, Service of Neurosurgery, Seville, Spain; 10Institute of Child Health, Developmental Biology and Cancer Programme Birth Defects Research Centre, University College London, London, United Kingdom
Craniopharyngiomas are rare benign epithelial tumors derived from remains of Rathke’s pouch. They are more prevalent in childhood, adolescence, and adults <50 years, and, commonly, are usually diagnosed after being associated with serious comorbidities when the development of the tumor is already advanced. To date, first-line therapy is usually surgery, but frequently the resection is not complete, causing high rates of recurrence. Therefore, the identification of new diagnostic and prognostic biomarkers as well as therapeutic tools to improve the management of patient with craniopharyngiomas is necessary. In recent years, a growing evidence indicates that defects in the splicing process are frequent in tumor pathologies, leading to the appearance of altered spliceosome components (SCs), splicing factors (SFs) and/or aberrant splicing variants (SVs; generated by alternative splicing), which are associated to the development, progression and aggressiveness of various cancer types. Based on the information described above, the aim of this study was to establish the expression profile of key splicing machinery components [major and minor spliceosome machinery (n = 13 and 4, respectively) and 28 relevant SFs] in craniopharyngiomas (primary and recurrent tumors; n = 36) compared with control samples [normal pituitary glands (NPs, n = 11)] using a microfluidic qPCR-array, to explore their potential dysregulation and identify specific components of this machinery that could serve as diagnostic and/or prognostic biomarkers as well as therapeutic targets for this pathology. Expression of a substantial number of components of the splicing machinery and SFs were drastically altered in craniopharyngiomas vs NPs, and, also when primary vs recurrent craniopharyngiomas were exclusively compared. Bioinformatic analyses identified RAVER1, RBM22, FBP11 and PRP8 as the most discriminating diagnostic factors of craniopharyngiomas vs NPs. These results were corroborated in two external cohorts (i.e. human and ACP-like mouse model). Furthermore, expression levels of some of these components were associated with key clinical parameters suggesting a potential patho-physiological role of these splicing components in craniopharyngiomas. Finally, the in vitro modulation of RAVER1 and PRP8 (the most relevant splicing component identified) in primary craniopharyngiomas-derived cell cultures revealed a critical role of these factors in craniopharyngiomas proliferation. Altogether, the expression of key splicing machinery components and associated SFs is dysregulated in craniopharyngiomas, which provides an original approach to identify novel diagnostic and/or prognostic biomarkers and new targets with therapeutic potential in this poorly known disease with multiple endocrine comorbidities.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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