  We have extended our previously developed 3D multi-scale agent-based brain
tumor model to simulate cancer heterogeneity and to analyze its impact across
the scales of interest. While our algorithm continues to employ an epidermal
growth factor receptor (EGFR) gene-protein interaction network to determine the
cells' phenotype, it now adds an explicit treatment of tumor cell adhesion
related to the model's biochemical microenvironment. We simulate a simplified
tumor progression pathway that leads to the emergence of five distinct glioma
cell clones with different EGFR density and cell 'search precisions'. The in
silico results show that microscopic tumor heterogeneity can impact the tumor
system's multicellular growth patterns. Our findings further confirm that EGFR
density results in the more aggressive clonal populations switching earlier
from proliferation-dominated to a more migratory phenotype. Moreover, analyzing
the dynamic molecular profile that triggers the phenotypic switch between
proliferation and migration, our in silico oncogenomics data display spatial
and temporal diversity in documenting the regional impact of tumorigenesis, and
thus support the added value of multi-site and repeated assessments in vitro
and in vivo. Potential implications from this in silico work for experimental
and computational studies are discussed.
