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

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 (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.

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

“…The expression of the representing leading edges depicted in heatmaps. f. Enrichment of the Proneural and Mesenchymal genesets in glioblastoma 18 , the Adrenergic and Mesenchymal genesets in neuroblastoma 2 and the mesenchymal vs NB stage 1 42 genesets in the down-and up-regulated genes upon SOX11 knockdown in IMR-32 and SOX11 overexpression in SH-EP. g. Enrichment of the GO genesets "GO Cell cell adhesion via plasma membrane adhesion molecules" and "GO Rho guanyl nucleotide exchange factor activity", in the upregulated genes upon SOX11 overexpression in SH-EP cells.…”

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

“…1c) for which ChIP-seq data were unavailable. Additionally, all enhancers contained binding motifs for TEAD4, a transcription factor implicated in a positive feedback loop with MYCN in MYCN-amplified neuroblastoma 20 . Two of the enhancers (e1, e2) also harbored canonical E-boxes, suggesting binding of MYCN at its own enhancers ( Supplementary Fig.…”

A Modular Master Regulator Landscape Determines the Impact of Genetic Alterations on the Transcriptional Identity of Cancer Cells

“…In addition, we provide both the Tumor Checkpoint MRs for the 112 tumor subtypes identified by the analysis as well as the MRs in the 24 MR-Blocks. These represent a comprehensive new collection of candidate tumor dependencies and therapeutic targets and outcome/drug-sensitivity biomarkers, several of which have been validated in previous studies, see for instance (Alvarez et al, 2018;Aytes et al, 2014b;Bisikirska et al, 2016;Carro et al, 2010;Rajbhandari et al, 2018b;Walsh et al, 2017). Given the pan-cancer nature of this work, in the following sections we will use different tumor types to highlight key advantages and novel findings made possible by the MOMA framework.…”

“…The Oncotecture hypothesis, which represents the cancer-specific counterpart of the Omnigene Hypothesis in human genetics (Boyle et al, 2017), is supported by a wealth of experimental evidence, from prostate cancer (Aytes et al, 2014b) and breast cancer (Rodriguez-Barrueco et al, 2015;Walsh et al, 2017), to glioblastoma (Carro et al, 2010), neuroblastoma (Rajbhandari et al, 2018a), and neuroendocrine tumors (Alvarez et al, 2018), see (Califano and Alvarez, 2017) for a comprehensive overview, but has not yet been comprehensively and systematically assessed across multiple tumor types.…”