Fig 1. Schematic of the simulated tumor environment.

The cellular environment is comprised of a continuous stromal tissue flanked on both sides by an epithelial layer. This epithelial layer is comprised of two cell types—Extracellular Matrix (pink) and Basal (navy blue). The epithelial layer secretes three main nutrients—glucose, glutamine and oxygen. The tumor cells (outlined in grey) are discrete entities that reside within the stromal tissue. Tumor cells take up glucose, glutamine and oxygen, and they secrete lactate into the stromal tissue. The diffusion of these nutrients is modeled using partial differential equations (illustrated by the gradient field, ranging from low concentration (blue) to a high concentration (red)). Each individual tumor cell has a detailed intracellular metabolic network, which takes the extracellular glucose, glutamine and oxygen concentrations as inputs to form ATP with lactate as a by-product of glycolysis. The dynamics of the metabolic network within each cell is modeled using ordinary differential equations. Cell sizes are not to scale.