Fig. 2

Flowchart of the computational modeling. Our model encapsulates four biological scales: molecular, cellular, microenvironmental and tissue scales. At the molecular scale, the EGFR signaling pathway, cell cycle and VEGFR signaling pathway were considered; at the cellular scale, tumor cells switch their phenotypes and endothelial cells migrate, proliferate or die; at the microenvironment scale, growth factors, nutrients (glucose and oxygen) and chemical inhibitors diffuse and exchange; at the tissue scale, new blood vessels grow and branch to form a microvasculature network. Intracellular signaling pathways were described using ODEs, and microenvironmental factors were described with PDEs. Cellular phenotype switching was simulated using a rule-based algorithm that is determined by both signaling pathways and microenvironmental factors. The treatment effects of EGFR inhibitors and VEGFR inhibitors were integrated into the model based on their mechanisms of action