1. Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma
- Author
-
Jo Vandesompele, Beatrice Salvatori, Richard A. Young, Brian J. Abraham, A. Thomas Look, Andrea Califano, Javed Khan, Presha Rajbhandari, Robert C. Seeger, Pieter Mestdagh, Jiyang Yu, Daniel Martinez, Claudia Capdevila, Rogier Versteeg, Nina Weichert-Leahey, Antonio Iavarone, Jun Wei, Jose Silva, Mark Yarmarkovich, Mariano J. Alvarez, Ruth Rodriguez-Barrueco, Anna Lasorella, Jo Lynne Harenza, John M. Maris, Shahab Asgharzadeh, Archana Iyer, Derek A. Oldridge, Jan Koster, Gonzalo Lopez, Katleen De Preter, Massachusetts Institute of Technology. Department of Biology, Abraham, Brian Joseph, Young, Richard A, Oncogenomics, and CCA - Cancer biology and immunology
- Subjects
Transcriptional Activation ,0301 basic medicine ,Proteasome Endopeptidase Complex ,Muscle Proteins ,Cell Cycle Proteins ,Regulatory Sequences, Nucleic Acid ,Biology ,Article ,Neuroblastoma ,03 medical and health sciences ,Cell Line, Tumor ,MYCN Positive ,medicine ,Humans ,Gene silencing ,TEAD4 ,neoplasms ,Neoplasm Staging ,Regulation of gene expression ,N-Myc Proto-Oncogene Protein ,Hippo signaling pathway ,Gene Expression Profiling ,Computational Biology ,Nuclear Proteins ,TEA Domain Transcription Factors ,medicine.disease ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,030104 developmental biology ,Oncology ,Cancer research ,RNA Interference ,N-Myc ,Acyltransferases ,Transcription Factors - 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
- Published
- 2018