Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma
Entity
UAM. Departamento de MedicinaPublisher
Ivyspring International PublisherDate
2019-07-07Citation
10.7150/thno.35458
Theranostics 9.17 (2019): 4946-4958
ISSN
1838-7640DOI
10.7150/thno.35458Funded by
This work was supported by the Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofounded by FEDER, [grant number PI14/00240, PI17/01796 to M.R., PI15/00783 to A.C], the Paradifference Foundation [no grant number applicable to M.R.], the ANR [ANR-2011-JCJC-00701 MODEOMAPP to AP.G-R], the European Union [FP7/2007-2013 n° 259735, Horizon 2020 n° 633983 to AP.G-R], Epigénétique et Cancer [EPIG201303 METABEPIC to AP.G-R], the the Ligue Nationale contre le Cancer ["Cartes d'Identité des Tumeurs (CIT) program" to AP.G-R], the Institut National du Cancer, the Direction Générale de l’Offre de Soins [PRT-K 2014, COMETE-TACTIC, INCa-DGOS_8663 to AP.G-R], the Deutsche Forschungsgemeinschaft (DFG) [CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease“ to F.B, M.F and G.E], the Rafael del Pino Foundation [Becas de Excelencia Rafael del Pino 2017 to B.C], the Severo Ochoa Excellence Programme [project SEV-2011-0191 to M.C-F], La Caixa Foundation [B004235 to JM.R-R], the Spanish Ministry of Education, Culture and Sport [grant number FPU16/05527 to M.S.], the Site de Recherche Intégré sur le Cancer-SIRIC [CARPEM Project to N.B.] and the AECC Foundation [grant number AIO15152858 to C.M-C]Project
Gobierno de España. PI14/00240; Gobierno de España. PI17/01796; Gobierno de España. PI15/00783; info:eu-repo/grantAgreement/EC/FP7/259735; info:eu-repo/grantAgreement/EC/H2020/633983/EU//ENSAT-HTEditor's Version
http://dx.doi.org/10.7150/thno.35458Subjects
multi-omic integration; pheochromocytoma/paraganglioma; miR-21-3p; liquid biopsy; prognostic biomarker; MedicinaNote
Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar y los autores pertenecientes a la UAMRights
© The author(s)Abstract
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
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Google Scholar:Calsina, Bruna
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Álvarez Escolá, María Cristina
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