2026-06-14T03:46:56Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/83202024-11-29T22:12:23Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Calsina, Bruna author Castro-Vega, Luis Jaime author Torres-Pérez, Rafael author Inglada Perez, Lucia author Currás-Freixes, Maria author Roldán-Romero, Juan María author Mancikova, Veronika author Letón, Rocío author Remacha, Laura author Santos, María author Burnichon, Nelly author Lussey-Lepoutre, Charlotte author Rapizzi, Elena author Graña, Osvaldo author Álvarez-Escolá, Cristina author de Cubas, Aguirre A author Lanillos, Javier author Cordero-Barreal, Alfonso author Martínez-Montes, Ángel M author Bellucci, Alexandre author Amar, Laurence author Fernandes-Rosa, Fabio Luiz author Calatayud, María author Aller, Javier author Lamas, Cristina author Sastre-Marcos, Júlia author Canu, Letizia author Korpershoek, Esther author Timmers, Henri J author Lenders, Jacques Wm author Beuschlein, Felix author Fassnacht-Capeller, Martin author Eisenhofer, Graeme author Mannelli, Massimo author Al-Shahrour, Fatima author Favier, Judith author Rodriguez Antona, Cristina author Cascon Soriano, Alberto author Montero-Conde, Cristina author Gimenez-Roqueplo, Anne-Paule author Robledo Mercedes, Mercedes author 2019-07-09 Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors. Theranostics. 2019 ;9(17):4946-4958 10.7150/thno.35458 1838-7640 1838-7640 Theranostics 31410193 http://hdl.handle.net/20.500.12105/8320 Liquid biopsy miR-21-3p Multi-omic integration Pheochromocytoma/paraganglioma Prognostic biomarker Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma