TY - JOUR
T1 - Cross-cohort analysis identifies a TEAD4–MYCN positive feedback loop as the core regulatory element of high-risk neuroblastoma
AU - Rajbhandari, Presha
AU - Lopez, Gonzalo
AU - Capdevila, Claudia
AU - Salvatori, Beatrice
AU - Yu, Jiyang
AU - Rodriguez-Barrueco, Ruth
AU - Martinez, Daniel
AU - Yarmarkovich, Mark
AU - Weichert-Leahey, Nina
AU - Abraham, Brian J.
AU - Alvarez, Mariano J.
AU - Iyer, Archana
AU - Harenza, Jo Lynne
AU - Oldridge, Derek
AU - de Preter, Katleen
AU - Koster, Jan
AU - Asgharzadeh, Shahab
AU - Seeger, Robert C.
AU - Wei, Jun S.
AU - Khan, Javed
AU - Vandesompele, Jo
AU - Mestdagh, Pieter
AU - Versteeg, Rogier
AU - Look, A. Thomas
AU - Young, Richard A.
AU - Iavarone, Antonio
AU - Lasorella, Anna
AU - Silva, Jose M.
AU - Maris, John M.
AU - Califano, Andrea
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85047866130&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29510988
U2 - https://doi.org/10.1158/2159-8290.CD-16-0861
DO - https://doi.org/10.1158/2159-8290.CD-16-0861
M3 - Article
C2 - 29510988
SN - 2159-8274
VL - 8
SP - 582
EP - 599
JO - Cancer discovery
JF - Cancer discovery
IS - 5
ER -