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Theranostics 2019; 9(17):4946-4958. doi:10.7150/thno.35458 This issue Cite

Research Paper

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

Bruna Calsina^1#, Luis Jaime Castro-Vega^2,3#, Rafael Torres-Pérez¹, Lucía Inglada-Pérez^1,4, Maria Currás-Freixes¹, Juan María Roldán-Romero¹, Veronika Mancikova¹, Rocío Letón¹, Laura Remacha¹, María Santos¹, Nelly Burnichon^2,3,5, Charlotte Lussey-Lepoutre^2,6, Elena Rapizzi⁷, Osvaldo Graña⁸, Cristina Álvarez-Escolá⁹, Aguirre A de Cubas¹, Javier Lanillos¹, Alfonso Cordero-Barreal¹, Ángel M Martínez-Montes¹, Alexandre Bellucci¹⁰, Laurence Amar^2,3,11, Fabio Luiz Fernandes-Rosa^2,3, María Calatayud¹², Javier Aller¹³, Cristina Lamas¹⁴, Júlia Sastre-Marcos¹⁵, Letizia Canu⁷, Esther Korpershoek¹⁶, Henri J Timmers¹⁷, Jacques WM Lenders^17,18, Felix Beuschlein^19,20, Martin Fassnacht-Capeller^21,22, Graeme Eisenhofer²³, Massimo Mannelli⁷, Fátima Al-Shahrour⁸, Judith Favier^2,3, Cristina Rodríguez-Antona^1,4, Alberto Cascón^1,4, Cristina Montero-Conde¹, Anne-Paule Gimenez-Roqueplo^2,3,5, Mercedes Robledo^1,4✉

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
^# These authors contributed equally

✉ Corresponding author: Dr. Mercedes Robledo, Hereditary Endocrine Cancer Group Leader, Centro Nacional de Investigaciones Oncológicas (CNIO), C/Melchor Fernandez Almagro, 3. 28029 - Madrid (Spain). Telephone number: +34 917328000 Ext 3320; e-mail: mrobledoes More

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

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