§ Corresponding Author

TheoreticalBiologyandMedicalModellingThisormattedPDFandfulltext(HTML)tingnon-smallcelllungcancerwithamultiscaleagent-basedmodelTheoreticalBiologyandMedicalModelling2007,4:50doi:10.1186/1742-4682-4-50ZhihuiWang(billwang@)LeZhang(adamzhan@)JonathanSagotsky(sagotsky@)ThomasSDeisboeck(deisboec@)ISSNArticletypeSubmissiondateAcceptancedatePublicationdateArticleURL1742-4682Research12June200721December200721December2007/content/4/1/edownloaded,printedanddistributedfreelyforanypurposes(seecopyrightnoticebelow).ormationaboutpublishingyourresearchinTBiomedoranyBioMedCentraljournal,goto/info/instructions/ForinformationaboutotherBioMedCentralpublicationsgoto/©2007Wangetal.,anopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Simulating non-small cell lung cancer with a

multiscale agent-based model

Zhihui Wang, Le Zhang, Jonathan Sagotsky, and Thomas S. Deisboeck

§

Complex Biosystems Modeling Laboratory, Harvard-MIT (HST) Athinoula A.

Martinos Center for Biomedical Imaging, Massachusetts General Hospital,

Charlestown, MA 02129, USA

§Corresponding Author:

Thomas S. Deisboeck, M.D.

Complex Biosystems Modeling Laboratory

Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging

Massachusetts General Hospital-East, 2301

Bldg. 149, 13th Street

Charlestown, MA 02129

Tel: 617-724-1845

Fax: 617-726-7422

Email: deisboec@

Email addresses:

ZW: billwang@

LZ:

adamzhan@

JS:

sagotsky@

TSD:

deisboec@

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Abstract

Background

The epidermal growth factor receptor (EGFR) is frequently overexpressed in many

cancers, including non-small cell lung cancer (NSCLC). In silico modeling is

considered to be an increasingly promising tool to add useful insights into the

dynamics of the EGFR signal transduction pathway. However, most of the previous

modeling work focused on the molecular or the cellular level only, neglecting the

crucial feedback between these scales as well as the interaction with the

heterogeneous biochemical microenvironment.

Results

We developed a multiscale model for investigating expansion dynamics of NSCLC

within a two-dimensional in silico microenvironment. At the molecular level, a

specific EGFR-ERK intracellular signal transduction pathway was implemented.

Dynamical alterations of these molecules were used to trigger phenotypic changes at

the cellular level. Examining the relationship between extrinsic ligand concentrations,

intrinsic molecular profiles and microscopic patterns, the results confirmed that

increasing the amount of available growth factor leads to a spatially more aggressive

cancer system. Moreover, for the cell closest to nutrient abundance, a phase-transition

emerges where a minimal increase in extrinsic ligand abolishes the proliferative

phenotype altogether.

Conclusions

Our in silico results indicate that in NSCLC, in the presence of a strong extrinsic

chemotactic stimulus (and depending on the cell’s location) downstream EGFR-ERK

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signaling may be processed more efficiently, thereby yielding a migration-dominant

cell phenotype and overall, an accelerated spatio-temporal expansion rate.

Background

Non-small cell lung cancer (NSCLC) remains at the top of the list of cancer-related

deaths in the United States [1]. The epidermal growth factor receptor (EGFR) is

frequently overexpressed in NSCLC [2, 3]. Binding of epidermal growth factor (EGF)

or transforming growth factor alpha (TGF