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  • Opinion
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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.

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Figure 1: The architecture of tumour checkpoints.
Figure 2: Dysregulation of homeostatic control following malignant transformation and activation of dystasis control mechanisms that are responsible for the stability of tumour cell state.
Figure 3: Diverse genetic alterations in upstream pathways contribute to aberrant NF-κB activity in DLBCL.
Figure 4: Protein activity inference from the expression of its regulatory targets.
Figure 5: Tumour checkpoint architecture of the mesenchymal subtype of glioblastoma.

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Acknowledgements

This work was supported by the National Cancer Institute (NCI) Cancer Target Discovery and Development Program (1U01CA168426), NCI Outstanding Investigator Award (R35CA197745) for A.C., NCI Research Centers for Cancer Systems Biology Consortium (1U54CA209997) and the NIH instrumentation grants (S10OD012351 and S10OD021764).

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Correspondence to Andrea Califano.

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A.C. is founder of DarwinHealth, Inc. M.J.A. has been employed by DarwinHealth, Inc. since March 2016.

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DATABASES

CCLE

FURTHER INFORMATION

The Cancer Genome Atlas

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Glossary

Bayesian networks

Probabilistic models representing the probabilities and conditional probabilities of variables representing nodes in a directed acyclic graph, that is, a type of network with nodes connected by directionally defined edges, usually represented as arrows, with no circular paths (cycles). This model is often used to determine the probability of an unknown event corresponding to one node as a function of the probability of other known events in the network.

Dystatic

Describes the aberrant processes responsible for implementing and maintaining a stable disease state, independent of most genetic, epigenetic and environmental perturbations.

Feed-forward loops

Regulatory structures in which a gene product (A) regulates a second gene product (B) and, together, A and B regulate one or more target gene products. These structures constitute a directed acyclic graph.

Homeostasis

The set of regulatory processes that ensures the overall stability of a system state, independent of endogenous and exogenous variables.

Interactomes

Sets of molecular interactions that constitute the regulatory logic of cells representative of a specific tissue and organism.

Isobologram

A two-dimensional map representing the viability of a cell following perturbation with a combination of two compounds. Each isobologram axis represents the concentration of an individual compound. This diagram is used to quantitatively assess whether the effect of the compound pair is additive, synergistic or antagonistic. This assessment is based on whether the isoboles (that is, curves in the diagram representing isopotency of the combination) are linear or nonlinear. Linear isoboles indicate additive behaviour, whereas nonlinear isoboles indicate synergistic (supra-additive) or antagonistic (sub-additive) behaviour.

Master regulator

(MR). Type of protein participating in a modular regulatory structure (that is, tumour checkpoint), the aberrant activity of which is both necessary and sufficient for tumour cell state implementation and maintenance and which directly controls the transcriptional state of a tumour cell.

Multiple hypothesis testing

When a test is repeated multiple times for — instance, a pair of dice are thrown multiple times — the probability of an outcome must be adjusted. This is a common problem in genetics, for example, where a large number of loci are tested to assess whether they are mutated in a cancer cohort, thus increasing the overall probability that any one of them may be mutated by chance.

Oncogene addiction hypothesis

The hypothesis that tumours become dependent on the aberrant activity of proteins encoded by mutated oncogenes and that pharmacological inhibition of these proteins will cause tumour demise.

Oncotecture

The regulatory architecture responsible for implementing tumour dystasis, comprising one or more tumour checkpoints that are responsible for integrating the effect of multiple mutations and aberrant signals in their upstream pathways to implement a conserved repertoire of downstream transcriptional programmes that are necessary and sufficient for tumour phenotype presentation.

Regulatory logic

The full complement of transcriptional, post-transcriptional and post-translational molecular interactions that determine cell behaviour.

Regulons

The full complement of transcriptional targets that are regulated by a protein. These can include either direct physical targets, for transcription factors and cofactors, or indirect targets for signal transduction.

Reverse engineering

Systematic dissection of the molecular interactions that comprise the regulatory logic of the cell.

Sample barcoding

A technique enabling incorporation of a predefined nucleic acid sequence (barcode) to tag either DNA or RNA molecules coming from a common sample so that they can be sequenced as a pool while retaining the ability to deconvolute which sample they came from.

Silhouette score

A measure, from −1 to 1, of how similar an object is to its own cluster compared with the closest other cluster.

Synthetic lethal

An interaction between two genes in which knockout of either gene in isolation has no (or minimal) negative impact on cell viability whereas knockout of both genes is lethal.

Tissue microarrays

(TMAs). Paraffin blocks in which up to 1,000 separate tissue cores are embedded in a grid to support multiplexed immunohistological analyses.

Tumour checkpoint

A small, autoregulated module comprising one or more master regulator (MR) proteins, the concerted activity of which is both necessary and sufficient for the implementation and maintenance of a tumour cell state.

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Califano, A., Alvarez, M. The recurrent architecture of tumour initiation, progression and drug sensitivity. Nat Rev Cancer 17, 116–130 (2017). https://doi.org/10.1038/nrc.2016.124

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