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Cancer Discov. 2018 May;8(5):582-599. doi: 10.1158/2159-8290.CD-16-0861. Epub 2018 Mar 6.

Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma.

Author information

1
Department of Systems Biology, Columbia University, New York, New York.
2
Department of Biological Sciences, Columbia University, New York, New York.
3
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
4
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
5
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
6
Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
7
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
8
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
9
Center for Medical Genetics & Cancer Research Institute Ghent (CRIG), Ghent University, Gent, Belgium.
10
Department of Oncogenomics, Academic Medical Center, Amsterdam, the Netherlands.
11
Division of Hematology/Oncology, Saban Research Institute, The Children's Hospital Los Angeles, Los Angeles, California.
12
Keck School of Medicine, University of Southern California, Los Angeles, California.
13
Genetics Branch, Oncogenomics Section, Center for Cancer Research, NIH, Bethesda, Maryland.
14
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
15
Department of Neurology and Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, New York.
16
Department of Pediatrics and Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, New York.
17
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. ac2248@cumc.columbia.edu maris@chop.edu.
18
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
19
Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
20
Department of Systems Biology, Columbia University, New York, New York. ac2248@cumc.columbia.edu maris@chop.edu.
21
Department of Biomedical Informatics, Columbia University, New York, New York.
22
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York.
23
Herbert Irving Comprehensive Cancer Center and J.P. Sulzberger Columbia Genome Center, Columbia University, New York, New York.
#
Contributed equally

Abstract

High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module-centered around a TEAD4-MYCN positive feedback loop-emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4-MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582-99. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.

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