ECE2024 Poster Presentations Pituitary and Neuroendocrinology (120 abstracts)
Comprehensive clinical, transcriptomic, and functional relevance of the telomerase-shelterin system in pituitary tumors and craniopharyngiomas
Ana S. De la Rosa-Herencia 1,2,3,4 , Miguel E. G-Garcia 1,2,3,4 , Álvaro Flores-Martínez 1,2,3,4 , María Ortega Bellido 1,2,3,4 , Ignacio Gil-Duque 1,2,3,4 , José H-Hernández 1,2,3,4 , David Cano 5 , Antonio Picó 6 , Araceli García-Martínez 1,2,3 , Justo P. Castaño 1,2,3,4 , Manuel D. Gahete 1,2,3,4 , María A. Gálvez-Moreno 1,4,7 , Alfonso Soto-Moreno 5 , Antonio C. Fuentes-Fayos 1,2,3,4 & Raúl M. Luque Huertas 1,2,3,4
1Maimónides Biomedical Research Institute (IMIBIC), Córdoba, Spain; 2University of Cordoba, Department of Cell Biology, Physiology and Immunology, Córdoba, Spain; 3CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Córdoba, Spain; 4Reina Sofia University Hospital (HURS), Córdoba, Spain; 5Hospital Universitario Virgen del Rocío (HUVR), Department of Neurosurgery, Seville, Spain; 6Endocrinology & Nutrition Service, University Hospital, Alicante, Spain; 7Service of Endocrinology and Nutrition, HURS, Córdoba, Spain
Intracranial Tumors comprise a diverse group of endocrine-related tumors [ERTs; e.g. craniopharyngiomas (CPs) and pituitary-tumors (PTs)], representing significant challenges for the diagnosis/prognosis/treatment of patients, their families and health systems due to their heterogeneity, associated neurological impairment and endocrine comorbidities. However, despite recent advances, the current treatment (e.g. surgery plus irradiation in CPs, pharmacological treatment with somatostatin/dopamine-agonists in PTs) originates adverse neurological effects, and drugs are not sufficiently effective in reducing the tumor mass size in a high proportion of cases. Therefore, the identification of novel therapeutic avenues to treat these devastating ERTs are urgently needed. Concretely, the Telomerase/Shelterin (TEL-SHEL) system, responsible for telomere maintenance, has been implicated in various cellular processes associated to cancer development/progression/aggressiveness. However, its interplay in the malignancy process of CPs and PTs remains poorly explored. Therefore, we aimed to analyze the: 1) expression of 17 critical TEL-SHEL components in CPs (n=60) and different PT types (n=152) compared to non-tumor pituitary tissues (n=10), using a microfluidic-array based on qPCR-technology; and 2) potential antitumor effects of modulating telomerase-activity and telomere-length through pharmacological modulation using BIBR1532 and in vitro cellula models. A profound dysregulation in the expression pattern of TEL-SHEL components was demonstrated in CPs and PTs. Notably, TERF2IP and TNKS were downregulated in CPs in three different human cohorts. Interestingly, enrichment analysis revealed a robust correlation between the low expression of TERF2IP and key cellular processes, such as the Wnt/β-catenin-pathway. Similarly, a significant alteration of the molecular profile TEL-SHEL was also observed in PTs, especially in somatotropinomas and corticotropinomas, but not in non-funcitoning PTs. Furthermore, BIBR1532-treatment showed a dose-dependent effect in different functional parameters in primary patient-derived cell-cultures and cell-lines [GH3 (somatotropinoma model) and AtT20 (corticotropinoma) models], including a reduction in cell-proliferation rates and stem-cell capacity. Altogether, we demonstrated a profound dysregulation of different key components of the TEL-SHEL system in CPs and PTs vs control samples, wherein some of these alterations may have clinical and/or functional relevance to improve the diagnosis/prognosis and management of these heterogeneous ERTs. Moreover, we demonstrated that the pharmacological modulation of the TEL-SHEL complex (using BIBR1532) exerted antitumoral effects in different ERTs, offering a clinically relevant opportunity that should be tested for use in humans.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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