Cross-scale, cross-pathway evaluation using an agent-based non-small cell lung cancer model.
We present a multiscale agent-based non-small cell lung cancer model that consists of a 3D environment with which cancer cells interact while processing phenotypic changes. At the molecular level, transforming growth factor beta (TGFbeta) has been integrated into our previously developed in silico model as a second extrinsic input in addition to epidermal growth factor (EGF). The main aim of this study is to investigate how the effects of individual and combinatorial change in EGF and TGFbeta concentrations at the molecular level alter tumor growth dynamics on the multi-cellular level, specifically tumor volume and expansion rate. Our simulation results show that separate EGF and TGFbeta fluctuations trigger competing multi-cellular phenotypes, yet synchronous EGF and TGFbeta signaling yields a spatially more aggressive tumor that overall exhibits an EGF-driven phenotype. By altering EGF and TGFbeta concentration levels simultaneously and asynchronously, we discovered a particular region of EGF-TGFbeta profiles that ensures phenotypic stability of the tumor system. Within this region, concentration changes in EGF and TGFbeta do not impact the resulting multi-cellular response substantially, while outside these concentration ranges, a change at the molecular level will substantially alter either tumor volume or tumor expansion rate, or both. By evaluating tumor growth dynamics across different scales, we show that, under certain conditions, therapeutic targeting of only one signaling pathway may be insufficient. Potential implications of these in silico results for future clinico-pharmacological applications are discussed.
Wang
Zhihui
Z
Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Birch
Christina M
CM
Sagotsky
Jonathan
J
Deisboeck
Thomas S
TS
D019295:Computational Biology / Q000379:methods*; D004815:Epidermal Growth Factor / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor