Simulating non-small cell lung cancer with a multiscale agent-based model

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.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 signaling may be processed more efficiently, thereby yielding a migration-dominant cell phenotype and overall, an accelerated spatio-temporal expansion rate.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 (TGFα) to the extracellular domain of EGFR produces a number of downstream effects that affect phenotypic cell behavior including proliferation, invasion, metastasis, and inhibition of apoptosis [4]. In particular, increasing the expression of these growth factors leads to EGFR hyperactivity [5,6], thus increases tumor cell motility and invasiveness, and finally enhances lung metastasis [7,8]. Since approximately 90% of all cancer deaths originate from the spread of primary tumor cells into the surrounding tissue [9], quantitative measurements of the relationship between the level of the growth factors and the resulting tumor