2024-03-29T04:39:57Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/83202023-10-13T09:48:50Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_2175
Repisalud
author
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
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Santos, María
author
Burnichon, Nelly
author
Lussey-Lepoutre, Charlotte
author
Rapizzi, Elena
author
Graña, Osvaldo
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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
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Fernandes-Rosa, Fabio Luiz
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Calatayud, María
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Aller, Javier
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Lamas, Cristina
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Sastre-Marcos, Júlia
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Canu, Letizia
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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
funder
Instituto de Salud Carlos III
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Ligue Nationale Contre le Cancer (Francia)
funder
Ministère de la Santé. Direction Generale de Offre de Soins (Francia)
funder
Deutsche Forschungsgemeinschaft (Alemania)
funder
Ministerio de Educación, Cultura y Deporte (España)
funder
Asociación Española Contra el Cáncer
2019-08-29T09:45:49Z
2019-08-29T09:45:49Z
2019-07-09
Theranostics. 2019 ;9(17):4946-4958
1838-7640
http://hdl.handle.net/20.500.12105/8320
31410193
10.7150/thno.35458
1838-7640
Theranostics
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.
eng
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
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/8320/1/Integrativemulti-omicsanalysisidentifies_2019.pdf
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https://repisalud.isciii.es/bitstream/20.500.12105/8320/7/Integrativemulti-omicsanalysisidentifies_2019.pdf.txt
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Integrativemulti-omicsanalysisidentifies_2019.pdf.txt