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From pathway to population – a multiscale model of juxtacrine EGFR-MAPK signalling

Walker, D.C., Georgopoulos, N.T. and Southgate, J. (2008) From pathway to population – a multiscale model of juxtacrine EGFR-MAPK signalling. BMC Systems Biology, 2 (1). p. 102. ISSN 1752-0509

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Most mathematical models of biochemical pathways consider either signalling events that take place within a single cell in isolation, or an 'average' cell which is considered to be representative of a cell population. Likewise, experimental measurements are often averaged over populations consisting of hundreds of thousands of cells. This approach ignores the fact that even within a genetically-homogeneous population, local conditions may influence cell signalling and result in phenotypic heterogeneity.We have developed a multi-scale computational model that accounts for emergent heterogeneity arising from the influences of intercellular signalling on individual cells within a population. Our approach was to develop an ODE model of juxtacrine EGFR-ligand activation of the MAPK intracellular pathway and to couple this to an agent-based representation of individual cells in an expanding epithelial cell culture population. This multi-scale, multi-paradigm approach has enabled us to simulate Extracellular signal-regulated kinase (Erk) activation in a population of cells and to examine the consequences of interpretation at a single cell or population-based level using virtual assays.


A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal. Extension of this model to a population consisting of hundreds to thousands of interacting virtual cells revealed that the activated Erk profile measured across the entire cell population was very different and may appear to contradict individual cell findings, reflecting heterogeneity in population density across the culture. This prediction was supported by immunolabelling of an epithelial cell population grown in vitro, which confirmed heterogeneity of Erk activation.


These results illustrate that mean experimental data obtained from analysing entire cell populations is an oversimplification, and should not be extrapolated to deduce the signal:response paradigm of individual cells. This multi-scale, multi-paradigm approach to biological simulation provides an important conceptual tool in addressing how information may be integrated over multiple scales to predict the behaviour of a biological system.

Item Type: Article
Copyright, Publisher and Additional Information: © 2008 Walker et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Institution: The University of Sheffield, The University of York
Academic Units: The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Computer Science (Sheffield)
The University of York > Biology (York)
Depositing User: Sheffield Import
Date Deposited: 08 Oct 2009 11:17
Last Modified: 08 Oct 2009 12:00
Published Version: http://www.biomedcentral.com/1752-0509/2/102
Status: Published
Publisher: BioMed Central
Identification Number: 10.1186/1752-0509-2-102
URI: http://eprints.whiterose.ac.uk/id/eprint/9757

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