THU080 Splicing Machinery Dysregulation As A Source Of Novel Diagnostic, Prognostic And Therapeutic Targets In Craniopharyngiomas

Abstract Disclosure: A.C. Fuentes-Fayos: None. M.E. Garcia-Garcia: None. D. Cano: None. A.J. Martínez-Fuentes: None. I. Di Caro: None. M.D. Gahete: None. J.P. Castaño: None. J.P. Martínez-Barbera: None. A. Soto-Moreno: None. M.A. Galvez-Moreno: None. J.M. Jimenez-Vacas: None. R.M. Luque: None. Craniopharyngiomas (CP) are relatively benign epithelial tumors that typically arise in the sellar/suprasellar region, and are classified in adamantinomatous (ACP) and papillary (PCP). Diagnosis is usually performed when tumor development is already advanced, and serious comorbidities are present. The first-line therapy is usually surgery, but frequently the resection is not complete, causing high recurrence rates. Therefore, the identification of alternative diagnostic/prognostic/therapeutic tools to improve CP management is necessary. Recently, growing evidence indicates that defects in the splicing-process are frequent in cancer, leading to the appearance of altered spliceosome components (SCs), splicing-factors (SFs) and/or aberrant splicing-variants (SVs), which are associated with the development/progression/aggressiveness of various cancer types. Therefore, our aim was to explore the putative oncogenic role of key splicing-related factors in CP 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 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, and associated with key clinical parameters suggesting a potential oncogenic role in CP. 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 factors in ACP. In fact, this overexpression induced the phosphorylation of MAPK and AKT pathways and reduced the phosphorylation JAK/STAT, NF-kB and TGFB that could be involved in the CP tumorigenesis. Finally, key SVs that are associated to CP development/progression (e.g., GNAS) were identified as potential oncogenic linkers with the observed splicing-machinery dysregulation. In conclusion, spliceosome is drastically altered in CP wherein some SFs could represent attractive novel diagnostic/prognostic and therapeutic targets for this endocrine pathology. Funding: Junta de Andalucia (PEER-0048-2020, Cofunded by EU-Programa Operativo FEDER 2014-2020). Presentation: Thursday, June 15, 2023