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

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Title: Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma
Authors: Duffy, David J.
Krstic, Aleksandar
Halasz, Melinda
Schwarzl, Thomas
Fey, Dirk
Mehta, Jai Prakash
Killick, Kate
Turriziani, Benedetta
Higgins, Desmond G
Kolch, Walter
et al.
Permanent link: http://hdl.handle.net/10197/9780
Date: 11-Dec-2015
Online since: 2019-04-03T08:15:26Z
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.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
Type of material: Journal Article
Publisher: Impact Journals
Journal: Oncotarget
Volume: 6
Issue: 41
Start page: 43182
End page: 43201
Copyright (published version): 2015 the Authors
Keywords: MYC (c-MYC)NeuroblastomaTranscriptional regulationmRNA sequencing (mRNA-seq)4sU-seq
DOI: 10.18632/oncotarget.6568
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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