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

David J. Duffy (Corresponding Author), Aleksandar Krstic, Melinda Halász, Thomas Schwarzl, Dirk Fey, Kristiina Iljin, Jai Prakash Rakash Mehta, Kate E. Killick, Jenny Whilde, Benedetta Turriziani, Saija Haapa-Paananen, Vidal Fey, et al.

Research output: Contribution to journalArticleScientificpeer-review

20 Citations (Scopus)

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 multilevel 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 ß-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.
Original languageEnglish
Pages (from-to)43182-43201
JournalOncotarget
Volume6
Issue number41
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

Fingerprint

Neuroblastoma
Oncogenes
Small Interfering RNA
Protein Interaction Maps
Gene Amplification
Chromatin Immunoprecipitation
Systems Analysis
Proteomics
Estradiol
Therapeutics
Genome
Mutation
Neoplasms

Keywords

  • 4sU-seq
  • MRNA sequencing
  • mRNA-seq
  • MYC
  • c-MYC
  • neuroblastoma
  • transcriptional regulation

Cite this

Duffy, David J. ; Krstic, Aleksandar ; Halász, Melinda ; Schwarzl, Thomas ; Fey, Dirk ; Iljin, Kristiina ; Mehta, Jai Prakash Rakash ; Killick, Kate E. ; Whilde, Jenny ; Turriziani, Benedetta ; Haapa-Paananen, Saija ; Fey, Vidal ; et al. / Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma. In: Oncotarget. 2015 ; Vol. 6, No. 41. pp. 43182-43201.
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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",
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 multilevel 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 {\ss}-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.",
keywords = "4sU-seq, MRNA sequencing, mRNA-seq, MYC, c-MYC, neuroblastoma, transcriptional regulation",
author = "Duffy, {David J.} and Aleksandar Krstic and Melinda Hal{\'a}sz and Thomas Schwarzl and Dirk Fey and Kristiina Iljin and Mehta, {Jai Prakash Rakash} and Killick, {Kate E.} and Jenny Whilde and Benedetta Turriziani and Saija Haapa-Paananen and Vidal Fey and {et al.}",
year = "2015",
doi = "10.18632/oncotarget.6568",
language = "English",
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Duffy, DJ, Krstic, A, Halász, M, Schwarzl, T, Fey, D, Iljin, K, Mehta, JPR, Killick, KE, Whilde, J, Turriziani, B, Haapa-Paananen, S, Fey, V & et al. 2015, 'Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma', Oncotarget, vol. 6, no. 41, pp. 43182-43201. https://doi.org/10.18632/oncotarget.6568

Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma. / Duffy, David J. (Corresponding Author); Krstic, Aleksandar; Halász, Melinda; Schwarzl, Thomas; Fey, Dirk; Iljin, Kristiina; Mehta, Jai Prakash Rakash; Killick, Kate E.; Whilde, Jenny; Turriziani, Benedetta; Haapa-Paananen, Saija; Fey, Vidal; et al.

In: Oncotarget, Vol. 6, No. 41, 2015, p. 43182-43201.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma

AU - Duffy, David J.

AU - Krstic, Aleksandar

AU - Halász, Melinda

AU - Schwarzl, Thomas

AU - Fey, Dirk

AU - Iljin, Kristiina

AU - Mehta, Jai Prakash Rakash

AU - Killick, Kate E.

AU - Whilde, Jenny

AU - Turriziani, Benedetta

AU - Haapa-Paananen, Saija

AU - Fey, Vidal

AU - et al., null

PY - 2015

Y1 - 2015

N2 - 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 multilevel 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 ß-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.

AB - 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 multilevel 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 ß-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.

KW - 4sU-seq

KW - MRNA sequencing

KW - mRNA-seq

KW - MYC

KW - c-MYC

KW - neuroblastoma

KW - transcriptional regulation

U2 - 10.18632/oncotarget.6568

DO - 10.18632/oncotarget.6568

M3 - Article

VL - 6

SP - 43182

EP - 43201

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 41

ER -