Universität zu Köln

Duffy, David J., Krstic, Aleksandar ORCID: 0000-0002-7128-5707, Halasz, Melinda ORCID: 0000-0002-6175-9630, Schwarzl, Thomas ORCID: 0000-0001-7697-7000, Fey, Dirk ORCID: 0000-0002-5558-0167, Iljin, Kristiina, Mehta, Jai Prakash, Killick, Kate, Whilde, Jenny, Turriziani, Benedetta, Haapa-Paananen, Saija, Fey, Vidal, Fischer, Matthias, Westermann, Frank, Henrich, Kai-Oliver, Bannert, Steffen, Higgins, Desmond G. and Kolch, Walter ORCID: 0000-0001-5777-5016 (2015). Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma. Oncotarget, 6 (41). S. 43182 - 43202. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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 beta-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Duffy, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krstic, Aleksandar UNSPECIFIED orcid.org/0000-0002-7128-5707 UNSPECIFIED Halasz, Melinda UNSPECIFIED orcid.org/0000-0002-6175-9630 UNSPECIFIED Schwarzl, Thomas UNSPECIFIED orcid.org/0000-0001-7697-7000 UNSPECIFIED Fey, Dirk UNSPECIFIED orcid.org/0000-0002-5558-0167 UNSPECIFIED Iljin, Kristiina UNSPECIFIED UNSPECIFIED UNSPECIFIED Mehta, Jai Prakash UNSPECIFIED UNSPECIFIED UNSPECIFIED Killick, Kate UNSPECIFIED UNSPECIFIED UNSPECIFIED Whilde, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Turriziani, Benedetta UNSPECIFIED UNSPECIFIED UNSPECIFIED Haapa-Paananen, Saija UNSPECIFIED UNSPECIFIED UNSPECIFIED Fey, Vidal UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Westermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Henrich, Kai-Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Bannert, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Higgins, Desmond G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolch, Walter UNSPECIFIED orcid.org/0000-0001-5777-5016 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-383575
DOI:	10.18632/oncotarget.6568
Journal or Publication Title:	Oncotarget
Volume:	6
Number:	41
Page Range:	S. 43182 - 43202
Date:	2015
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language N-MYC; GENE-EXPRESSION; C-MYC; PROLIFERATION; PATHWAY; GROWTH; DIFFERENTIATION; INHIBITION; FAMILY; DNA Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38357