Cross-cohort analysis identifies a TEAD4 ↔ MYCN positive-feedback loop as the core regulatory element of high-risk neuroblastoma.

Protein-protein interactions generated using Preppi (v1.0)

Protein-protein interactions generated using Preppi (v1.0) https://ctd2-dashboard.nci.nih.gov/dashboard/ 

Rajbhandari P, Lopez G, Capdevila C1, Salvatori B, Yu J, Rodriguez-Barrueco R, Martinez D, Yarmarkovich M, Weichert-Leahey N, Abraham BJ, Alvarez MJ, Iyer A, Harenza JL, Oldridge D, De Preter K, Koster J, Asgharzadeh S, Seeger RC, Wei JS, Khan J, Vandesompele J, Mestdagh P, Versteeg R, Look AT, Young RA, Iavarone A, Lasorella A, Silva JM, Maris JM, Califano A

Cancer Discovery

March 06, 2018

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 (MR) 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 co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.

Program:
CTD²
Program:
TARGET
Last updated: April 27, 2018