Agent-based modeling (ABM) is an in silico technique that is being used in a variety of research areas such as in social sciences, economics and increasingly in biomedicine as an interdisciplinary tool to study the dynamics of complex systems. Here, we describe its applicability to integrative tumor biology research by introducing a multi-scale tumor modeling platform that understands brain cancer as a complex dynamic biosystem. We summarize significant findings of this work, and discuss both challenges and future directions for ABM in the field of cancer research.

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.

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.