ECE2023 Oral Communications Oral Communications 7: Pituitary and Neuroendocrinology 2 (6 abstracts)
Pathophysiological role of splicing machinery in craniopharyngiomas: Novel source of diagnostic, prognostic and therapeutic biomarkers
Álvaro Flores-Martínez 1,2,3,4 , Antonio C. Fuentes-Fayos 1,2,3,4 , Miguel E. G-Garcia 1,2,3,4 , David Cano Gonzales 5 , Isidoro Di Caro 1,2,3,4 , Antonio Jesús Martínez-Fuentes 1,2,3,4 , Justo P. Castaño 1,2,3,4 , Manuel D. Gahete 1,2,3,4 , Juan Pedro Martínez-Barbera 6 , Alfonso Soto-Moreno 5 , María Ángeles Gálvez-Moreno 1,3,7 & Raul 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; 5Metabolism and Nutrition Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain; 6Institute of Child Health, Developmental Biology and Cancer, Birth Defects Research Centre, University College London, London, United Kingdom; 7Reina Sofia University Hospital (HURS), Service of Endocrinology and Nutrition, Cordoba, Spain
Craniopharyngiomas (CPs) are a relatively benign subtype of epithelial tumors that typically originate from the sellar and suprasellar regions of the brain. These endocrine tumors are classified as adamantinomatous (ACP) or papillary (PCP) based on their histological characteristics. Unfortunately, the diagnosis of CPs is frequently made at an advanced stage of tumor development, and therefore relevant associated comorbidities are often present. The first-line treatment is typically surgical intervention; however, complete resection is often not achieved leading to high rates of recurrence. Therefore, there is an urgent need to identify alternative diagnostic, prognostic, and therapeutic tools to improve the management of CPs. Recently, growing evidence indicates that RNA splicing-process is altered in different endocrine-related tumors which leads to the generation of altered spliceosome components (SCs), splicing factors (SFs), and/or aberrant splicing-variants (SVs) associated with cancer progression, aggressiveness and development. Therefore, our aim was to explore the putative oncogenic role of key splicing-related factors in CPs through: 1) interrogating the expression profile of key splicing machinery components in ACP (n=36) and PCP (n=4) vs control samples [n=11; normal-pituitaries (NP)]; and 2) implementing different bioinformatic and functional approaches (RNAseq and CP primary cell-cultures). Our results revealed a substantial number of SCs and SFs are drastically altered in ACP vs NP, and also when primary vs recurrent ACP were compared. Specifically, 4 SFs were identified as the most discriminating diagnostic/prognostic factors, being corroborated in additional human cohorts. These SFs were also associated with key clinical parameters suggesting a potential oncogenic role in CPs. Moreover, dysregulation of 2 of these SFs was also corroborated in RNAseq of an additional cohort of 18 ACP vs 3 NP. In vitro overexpression of these SFs in primary ACP-derived cells revealed a critical functional role of these SFs in ACP. In fact, the in vitro overexpression induced the phosphorylation of MAPK and AKT pathways and reduced the phosphorylation JAK/STAT, NF-kB and TGFB which might be associated with CP tumorigenesis. Finally, relevant SVs that are associated to CP development and progression (e.g., GNAS) were identified as potential oncogenic linkers with the observed splicing-machinery dysregulation. In conclusion, spliceosome is drastically altered in CPs, wherein some SFs could represent attractive novel diagnostic/prognostic and therapeutic targets for this endocrine pathology.
Volume 90
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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