The recurrent architecture of tumour initiation, progression and drug sensitivity

Abstract

Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.

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

“…Consistent with the recently proposed tumor checkpoint model (15), we elucidated a modular and hierarchical 10-protein architecture, responsible for the implementation of an aggressive neuroblastoma subtype (MYCNA) associated with aberrant activity of MYCN/MYC proteins. Experimental validation of these MR proteins confirmed their enrichment in MYCNA-subtype specific essential genes and their ability to regulate each other, as well as MYCNA-signature genes, through multiple autoregulatory loops, thus establishing their role as bona fide master regulators.…”

“…We have proposed that the stability of tumor-related phenotypes is controlled by tightly auto-regulated MR protein modules (tumor checkpoints) that mechanistically regulate the transcriptional state of the cancer cell (9, 15). To test this hypothesis, we assessed the ability of MYCNA-specific MRs to mechanistically regulate each other, as well as the MYCNA-subtype transcriptional signature.…”

“…MR proteins have been shown to elicit either essentiality or synthetic lethality in several cancers (8–16). Critically, aberrant activity of tumor checkpoint MRs arises from one or more genetic alterations in their upstream pathways (14, 17), thus providing a rationale for the heterogeneous mutational landscape of tumors with highly similar transcriptional states (15). MR proteins have been shown to represent critical molecular tumor vulnerabilities that can be effectively targeted pharmacologically in several human malignancies (10, 11, 16, 18, 19), thus providing novel therapeutic opportunities.…”

Severe asthma: phenotyping to endotyping or vice versa?

“…The pattern of multiple activation reported by KUO et al [19] is reminiscent of the presence of a potential "master regulator," as recently described by CALIFANO and ALVAREZ [31] in cancer literature. This approach seems to be working for cancer, a disease with a complex genetic background.…”

Pancreas Cancer Precision Treatment Using Avatar Mice from a Bioinformatics Perspective

“…Gene regulatory network analysis is capable of elucidating master regulator proteins involved in bottlenecks of the transcriptional programs [53]. Theoretically, these master regulator proteins play a central role in the transcriptional architecture of the tumor by canalizing the upstream effects of oncogenic driver mutations and other aberrant signals to the rest of the network downstream.…”