Format

Send to

Choose Destination
Theranostics. 2019 Jul 9;9(17):4946-4958. doi: 10.7150/thno.35458. eCollection 2019.

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma.

Author information

1
Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
2
INSERM, UMR970, Paris-Cardiovascular Research Center, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.
3
Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
4
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
5
Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
6
Sorbonne Université, Pitié-Salpêtrière Hospital, Department of nuclear medicine, Paris, France.
7
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
8
Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
9
Servicio de Endocrinología y Nutrición, Hospital Universitario La Paz, Madrid, Spain.
10
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
11
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France.
12
Department of Endocrinology and Nutrition Service, Hospital Universitario 12 de Octubre, Madrid, Spain.
13
Department of Endocrinology, Puerta de Hierro University Hospital, Madrid, Spain.
14
Department of Endocrinology, Albacete University Hospital Complex, Albacete, Spain.
15
Department of Endocrinology, Virgen de la Salud Hospital-Toledo Hospital Complex, Toledo, Spain.
16
Department of Pathology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
17
Department of Internal Medicine, Radboud University Medical Centre, 6525 HP Nijmegen, The Netherlands.
18
Department of Medicine III, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
19
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
20
Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland.
21
Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, University of Würzburg, Germany.
22
Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany.
23
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Abstract

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.

KEYWORDS:

liquid biopsy; miR-21-3p; multi-omic integration; pheochromocytoma/paraganglioma; prognostic biomarker

Supplemental Content

Full text links

Icon for Ivyspring International Publisher Icon for PubMed Central
Loading ...
Support Center