ECE2023 Rapid Communications Rapid Communications 6: Endocrine-related Cancer (6 abstracts)
Refocusing on somatostatin receptors as clinical targets in pheochromocytomas and paragangliomas
Víctor García Vioque 1,2,3 , María Trinidad Moreno Montilla 1,2,4 , Ricardo Blázquez Encinas Rey 4,5,6 , Federica Mangili 4,5,6,7 , Ángel Mario Martínez Montes 8 , Emilia Alors-Pérez 4,5,6 , Michael D Culler 9 , Sergio Pedraza-Arevalo 4,5,6 , Mercedes Robledo 8,10 , Justo P. Castaño 4,5,6,11 & Alejandro Ibañez Costa 4,5,6
1Maimonides Biomedical Research Institute of Cordoba, Córdoba, Spain; 2University of Córdoba (UCO), Cell Biology, Physiology and Immunology, Córdoba, Spain; 3Reina Sofia University Hospital (HURS), Córdoba, Spain; 4Reina Sofia University Hospital (HURS), Cordoba, Spain; 5Maimonides Biomedical Research Institute of Cordoba, Cordoba, Spain; 6University of Cordoba (UCO), Cell Biology, Physiology and Immunology, Cordoba, Spain; 7University of Milan, Department of Clinical Sciences and community Health, Milan, Italy; 8Spanish National Cancer Research Centre (CNIO), Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Madrid, Spain; 9Amolyt Pharma, Cambridge, United States; 10Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain; 11CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms (NENs) that arise in the adrenal medulla and paraganglia, respectively. As occurs in the rest of NENs, PPGLs commonly present a high density of somatostatin receptors (SSTs) on their membrane. However, unlike in most NENs, somatostatin analogues (SSAs) do not represent a suitable therapeutic target in PPGLs, and the mechanisms underlying this mismatch are still unclear. In this study, we aim to identify the molecular elements and processes involved in the lack of response of PPGL to SSAs, with the ultimate goal of sensitizing PPGL to these drugs. To this end, we first explored by RNA-seq analysis two cohorts of 204 and 95 samples, and the TCGA dataset, focusing on determining the profile of SSTs in PPGL samples and the differences in their expression depending on driver genes mutations. Then, in vitro assays were performed using two cell lines representative of the pathology: rat PC-12 cells and human SK-N-AS cells (wildtype and SDHB-KD). We determined their response to somatostatin, cortistatin, SSAs (octreotide and pasireotide) and specific SSTs agonists on different functional assays, including cell proliferation, colony formation and wound healing, as well as key intracellular signaling pathways. Transcriptomic analyses revealed a marked difference in the expression pattern of SSTs between the different PPGL molecular clusters, with a clear divergence in the type of SSTs expressed across the mutated driver genes. In striking contrast, we did not observe any antitumor effect in response to somatostatin, cortistatin or SSAs in vitro. Interestingly, however, the use of selective agonists for each SST revealed antiproliferative effects in human cells, specifically in those lacking SDHB, whereas, no significant effects were observed on colony formation and migration assays. Current analyses are focused on the elements downstream SST signaling. Taken together, our results suggest previously unrecognized molecular associations between the SST system and PPGL subtypes and invite to further explore the underlying mechanisms behind their lack of response to SSA therapy.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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