Abstract
Original language | English |
---|---|
Pages (from-to) | 43182-43201 |
Journal | Oncotarget |
Volume | 6 |
Issue number | 41 |
DOIs | |
Publication status | Published - 2015 |
MoE publication type | A1 Journal article-refereed |
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Keywords
- 4sU-seq
- MRNA sequencing
- mRNA-seq
- MYC
- c-MYC
- neuroblastoma
- transcriptional regulation
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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 journal › Article › Scientific › peer-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 -