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  • Review Article
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The dynamic control of signal transduction networks in cancer cells

Nature Reviews Cancer volume 15, pages 515–527 (2015)Cite this article

Subjects

Key Points

  • Signal transduction networks (STNs) regulate fundamental biological processes by integrating and computing external and internal signals to adjust cellular physiology to changing environmental and intrinsic cues.

  • Much of the computing function of STNs is carried out by small network modules that function as switches, noise filters, oscillators, signal integrators and distributors, combinatorial ensembles of which can translate complex molecular reactions into accurate biological responses.

  • STN components are frequently affected in cancer by genetic mutations or epigenetic silencing, causing STN rewiring that modulates the biological effects of these genetic and epigenetic changes.

  • These STN alterations in cancer dynamically integrate intrinsic genetic and epigenetic changes with external stress factors, such as drug or radiation treatments, generating new network states that can profoundly change the ability of the cancer cells to survive, grow and spread.

  • Mathematical and computational modelling are powerful tools for the analysis of STNs and STN aberrations and for understanding and predicting the effects of mutations and therapeutic interventions in cancer.

Abstract

Cancer is often considered a genetic disease. However, much of the enormous plasticity of cancer cells to evolve different phenotypes, to adapt to challenging microenvironments and to withstand therapeutic assaults is encoded by the structure and spatiotemporal dynamics of signal transduction networks. In this Review, we discuss recent concepts concerning how the rich signalling dynamics afforded by these networks are regulated and how they impinge on cancer cell proliferation, survival, invasiveness and drug resistance. Understanding this dynamic circuitry by mathematical modelling could pave the way to new therapeutic approaches and personalized treatments.

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Figure 1: Examples of the role of feedback control in signal transduction networks.
Figure 2: Dynamic control of EMT.
Figure 3: Pathway crosstalk.
Figure 4: Transcriptional dynamics.
Figure 5: Network-mediated mechanisms of drug resistance.

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Acknowledgements

This work was supported by the Science Foundation Ireland under grant number 06/CE/B1129 and the European Union FP7 (Seventh Framework Programme for Research and Technological Development) under grant number 259348–2 ASSET (Analysing and Striking the Sensitivities of Embryonal Tumours).

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Authors and Affiliations

  1. Systems Biology Ireland, University College Dublin,

    Walter Kolch, Melinda Halasz & Boris N. Kholodenko

  2. Conway Institute of Biomolecular & Biomedical Research, University College Dublin,

    Walter Kolch & Boris N. Kholodenko

  3. School of Medicine and Medical Science, University College Dublin, Dublin, 4, Belfield, Ireland

    Walter Kolch & Boris N. Kholodenko

  4. Roche Moscow Limited, Business Center Neglinnaya Plaza, Building 2, Trubnaya Square, Moscow, 107031, Russia

    Marina Granovskaya

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  1. Walter Kolch
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  2. Melinda Halasz
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  4. Boris N. Kholodenko
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Correspondence to Walter Kolch or Boris N. Kholodenko.

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Glossary

Cybernetics

A field of science that studies the properties and topology of systems that receive, store and process information to use it for control purposes.

Network topology

The structure of a network as determined by the nodes (components) and edges (connections between them).

Bistability (or multistability)

Refers to a system having two (or more) stable states. For instance, a switch is a bistable system that can be in either an ON or an OFF state.

Feedback loops

Network motifs in which a downstream molecule (B) affects the activity of its upstream regulator (A). Feedback loops can be negative (where B inhibits A) or positive (where B activates A).

'AND' gate

A function that requires two simultaneous inputs to elicit an output. By contrast, an 'OR' gate requires only one of two possible inputs to produce an output.

Amplifier

A device or circuit that increases the amplitude of an input signal. For example, kinase cascades, in which a kinase phosphorylates and activates another kinase, can act as amplifiers if the downstream kinase is more abundant than the upstream kinase. Amplifiers can generate linear or nonlinear gains in signal strengths.

Negative-feedback amplifier

(NFA). A circuit in which the output of an amplifier is linked back to the input through a negative-feedback loop. In this constellation, the strength of the negative feedback determines the dynamic behaviour of the circuit. The NFA structure is common to the ubiquitous MAPK pathways, in which a three-tiered kinase cascade functions as an amplifier and the terminal MAPK feedback inhibits the first kinase in the cascade.

Noise-buffering signal integrator

A network circuit in which two components are linked by mutually negative feedbacks that only allow monostable states: that is, when one component is ON the other is OFF. This circuit can integrate signals while efficiently buffering noise, as the output is a digital ON or OFF state.

Driver mutation

A mutation that is necessary for, and drives the pathogenesis of, a disease. By contrast, a passenger mutation is a mutation that occurs coincidentally and is dispensable for pathogenesis.

Feedforward loops

Network motifs in which an upstream regulator (A) affects the activity of a downstream node (C) directly as well as indirectly via an intermediate node (B). If both pathways connecting A to C activate C, the feedforward loop is called coherent. If one pathway is inhibitory and the other stimulatory, the feedforward loop is termed incoherent.

Coincidence detector

A device that detects whether two or more signals coincide in time and/or space. For example, an 'AND' gate can function as a coincidence detector.

Pulsatile

Indicates a pulsating or rhythmic change in the amplitude of a signal input or output response.

Toggle switch

An ON or OFF switch that is operated by 'flipping' a lever. In network biology, this term is used to indicate configurations in which a certain input condition, like a lever, switches an output state ON or OFF.

Chronotherapy

Refers to the timing of the application of a therapy to maximize its desired effects and/or minimize its side effects.

Multiscale modelling

Modelling of systems across different scales, such as atomistic, molecular, subcellular and cellular. Sometimes used to indicate that different modelling methods (for example, deterministic and stochastic methods) are combined in order to describe a system.

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Kolch, W., Halasz, M., Granovskaya, M. et al. The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer 15, 515–527 (2015). https://doi.org/10.1038/nrc3983

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