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 Calsina1#, Luis Jaime Castro-Vega2,3#, Rafael Torres-Pérez1, Lucía Inglada-Pérez1,4, Maria Currás-Freixes1, Juan María Roldán-Romero1, Veronika Mancikova1, Rocío Letón1, Laura Remacha1, María Santos1, Nelly Burnichon2,3,5, Charlotte Lussey-Lepoutre2,6, Elena Rapizzi7, Osvaldo Graña8, Cristina Álvarez-Escolá9, Aguirre A de Cubas1, Javier Lanillos1, Alfonso Cordero-Barreal1, Ángel M Martínez-Montes1, Alexandre Bellucci10, Laurence Amar2,3,11, Fabio Luiz Fernandes-Rosa2,3, María Calatayud12, Javier Aller13, Cristina Lamas14, Júlia Sastre-Marcos15, Letizia Canu7, Esther Korpershoek16, Henri J Timmers17, Jacques WM Lenders17,18, Felix Beuschlein19,20, Martin Fassnacht-Capeller21,22, Graeme Eisenhofer23, Massimo Mannelli7, Fátima Al-Shahrour8, Judith Favier2,3, Cristina Rodríguez-Antona1,4, Alberto Cascón1,4, Cristina Montero-Conde1, Anne-Paule Gimenez-Roqueplo2,3,5, Mercedes Robledo1,4✉

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

Citation:
Calsina B, Castro-Vega LJ, Torres-Pérez R, Inglada-Pérez L, Currás-Freixes M, Roldán-Romero JM, Mancikova V, Letón R, Remacha L, Santos M, Burnichon N, Lussey-Lepoutre C, Rapizzi E, Graña O, Álvarez-Escolá C, de Cubas AA, Lanillos J, Cordero-Barreal A, Martínez-Montes ÁM, Bellucci A, Amar L, Fernandes-Rosa FL, Calatayud M, Aller J, Lamas C, Sastre-Marcos J, Canu L, Korpershoek E, Timmers HJ, Lenders JWM, Beuschlein F, Fassnacht-Capeller M, Eisenhofer G, Mannelli M, Al-Shahrour F, Favier J, Rodríguez-Antona C, Cascón A, Montero-Conde C, Gimenez-Roqueplo AP, Robledo M. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics 2019; 9(17):4946-4958. doi:10.7150/thno.35458. https://www.thno.org/v09p4946.htm
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Abstract

Graphic 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


Citation styles

APA
Calsina, B., Castro-Vega, L.J., Torres-Pérez, R., Inglada-Pérez, L., Currás-Freixes, M., Roldán-Romero, J.M., Mancikova, V., Letón, R., Remacha, L., Santos, M., Burnichon, N., Lussey-Lepoutre, C., Rapizzi, E., Graña, O., Álvarez-Escolá, C., de Cubas, A.A., Lanillos, J., Cordero-Barreal, A., Martínez-Montes, Á.M., Bellucci, A., Amar, L., Fernandes-Rosa, F.L., Calatayud, M., Aller, J., Lamas, C., Sastre-Marcos, J., Canu, L., Korpershoek, E., Timmers, H.J., Lenders, J.WM., Beuschlein, F., Fassnacht-Capeller, M., Eisenhofer, G., Mannelli, M., Al-Shahrour, F., Favier, J., Rodríguez-Antona, C., Cascón, A., Montero-Conde, C., Gimenez-Roqueplo, A.P., Robledo, M. (2019). Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics, 9(17), 4946-4958. https://doi.org/10.7150/thno.35458.

ACS
Calsina, B.; Castro-Vega, L.J.; Torres-Pérez, R.; Inglada-Pérez, L.; Currás-Freixes, M.; Roldán-Romero, J.M.; Mancikova, V.; Letón, R.; Remacha, L.; Santos, M.; Burnichon, N.; Lussey-Lepoutre, C.; Rapizzi, E.; Graña, O.; Álvarez-Escolá, C.; de Cubas, A.A.; Lanillos, J.; Cordero-Barreal, A.; Martínez-Montes, Á.M.; Bellucci, A.; Amar, L.; Fernandes-Rosa, F.L.; Calatayud, M.; Aller, J.; Lamas, C.; Sastre-Marcos, J.; Canu, L.; Korpershoek, E.; Timmers, H.J.; Lenders, J.WM.; Beuschlein, F.; Fassnacht-Capeller, M.; Eisenhofer, G.; Mannelli, M.; Al-Shahrour, F.; Favier, J.; Rodríguez-Antona, C.; Cascón, A.; Montero-Conde, C.; Gimenez-Roqueplo, A.P.; Robledo, M. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics 2019, 9 (17), 4946-4958. DOI: 10.7150/thno.35458.

NLM
Calsina B, Castro-Vega LJ, Torres-Pérez R, Inglada-Pérez L, Currás-Freixes M, Roldán-Romero JM, Mancikova V, Letón R, Remacha L, Santos M, Burnichon N, Lussey-Lepoutre C, Rapizzi E, Graña O, Álvarez-Escolá C, de Cubas AA, Lanillos J, Cordero-Barreal A, Martínez-Montes ÁM, Bellucci A, Amar L, Fernandes-Rosa FL, Calatayud M, Aller J, Lamas C, Sastre-Marcos J, Canu L, Korpershoek E, Timmers HJ, Lenders JWM, Beuschlein F, Fassnacht-Capeller M, Eisenhofer G, Mannelli M, Al-Shahrour F, Favier J, Rodríguez-Antona C, Cascón A, Montero-Conde C, Gimenez-Roqueplo AP, Robledo M. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics 2019; 9(17):4946-4958. doi:10.7150/thno.35458. https://www.thno.org/v09p4946.htm

CSE
Calsina B, Castro-Vega LJ, Torres-Pérez R, Inglada-Pérez L, Currás-Freixes M, Roldán-Romero JM, Mancikova V, Letón R, Remacha L, Santos M, Burnichon N, Lussey-Lepoutre C, Rapizzi E, Graña O, Álvarez-Escolá C, de Cubas AA, Lanillos J, Cordero-Barreal A, Martínez-Montes ÁM, Bellucci A, Amar L, Fernandes-Rosa FL, Calatayud M, Aller J, Lamas C, Sastre-Marcos J, Canu L, Korpershoek E, Timmers HJ, Lenders JWM, Beuschlein F, Fassnacht-Capeller M, Eisenhofer G, Mannelli M, Al-Shahrour F, Favier J, Rodríguez-Antona C, Cascón A, Montero-Conde C, Gimenez-Roqueplo AP, Robledo M. 2019. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics. 9(17):4946-4958.

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