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Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma

David J. Duffy _, Aleksandar Krstic, Melinda Halasz, Thomas Schwarzl, Dirk Fey, Kristiina Iljin, Jai Prakash Mehta, Kate Killick, Jenny Whilde, Benedetta Turriziani, Saija Haapa-Paananen, Vidal Fey, Matthias Fischer, Frank Westermann, Kai-Oliver Henrich, Steffen Bannert, Desmond G. Higgins and Walter Kolch

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Oncotarget. 2015; 6:43182-43201. https://doi.org/10.18632/oncotarget.6568

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Abstract

David J. Duffy1,7,*, Aleksandar Krstic1,*, Melinda Halasz1,*, Thomas Schwarzl1,8,*, Dirk Fey1, Kristiina Iljin6, Jai Prakash Mehta1, Kate Killick1, Jenny Whilde1, Benedetta Turriziani1, Saija Haapa-Paananen6, Vidal Fey6, Matthias Fischer5, Frank Westermann4, Kai-Oliver Henrich4, Steffen Bannert4, Desmond G. Higgins1,2,3 and Walter Kolch1,2,3

1 Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland

2 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin, Ireland

3 School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland

4 Division of NB Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

5 Department of Paediatric Haematology and Oncology and Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany

6 VTT Technical Research Centre of Finland, Tietotie 2, Espoo, Finland

7 The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, Florida, USA

8 European Molecular Biology Laboratory (EMBL), Meyerhofstraße, Heidelberg, Germany

* These authors have contributed equally to this work

Correspondence to:

David J. Duffy, email:

Keywords: MYC (c-MYC), neuroblastoma, transcriptional regulation, mRNA sequencing (mRNA-seq), 4sU-seq

Received: November 15, 2015 Accepted: November 23, 2015 Published: December 11, 2015

Abstract

Despite intensive study, many mysteries remain about the MYCN oncogene’s functions. Here we focus on MYCN’s role in neuroblastoma, the most common extracranial childhood cancer. MYCN gene amplification occurs in 20% of cases, but other recurrent somatic mutations are rare. This scarcity of tractable targets has hampered efforts to develop new therapeutic options. We employed a multi-level omics approach to examine MYCN functioning and identify novel therapeutic targets for this largely un-druggable oncogene. We used systems medicine based computational network reconstruction and analysis to integrate a range of omic techniques: sequencing-based transcriptomics, genome-wide chromatin immunoprecipitation, siRNA screening and interaction proteomics, revealing that MYCN controls highly connected networks, with MYCN primarily supressing the activity of network components. MYCN’s oncogenic functions are likely independent of its classical heterodimerisation partner, MAX. In particular, MYCN controls its own protein interaction network by transcriptionally regulating its binding partners.

Our network-based approach identified vulnerable therapeutically targetable nodes that function as critical regulators or effectors of MYCN in neuroblastoma. These were validated by siRNA knockdown screens, functional studies and patient data. We identified β-estradiol and MAPK/ERK as having functional cross-talk with MYCN and being novel targetable vulnerabilities of MYCN-amplified neuroblastoma. These results reveal surprising differences between the functioning of endogenous, overexpressed and amplified MYCN, and rationalise how different MYCN dosages can orchestrate cell fate decisions and cancerous outcomes. Importantly, this work describes a systems-level approach to systematically uncovering network based vulnerabilities and therapeutic targets for multifactorial diseases by integrating disparate omic data types.


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