Fig 2. Schematic summarising the key interactions that are included in the agent based model.

A: Oxygen is supplied by blood vessels and consumed by stromal cells and tumour cells. Cell-cycle progression is determined by a cell’s local oxygen concentration: a cell may be ‘proliferative’ (and progress through its cell cycle), ‘hypoxic’ (the cell cycle is temporarily paused until oxygen concentrations return to a sufficiently high level) or ‘necrotic’ (the cell becomes necrotic cell and degrades). Cell cycles also pause if there is insufficient space available for proliferation. B: Macrophage behaviour depends on phenotype p, modulating their rates of tumour cell killing, EGF production, and chemotactic sensitivity to gradients of CSF-1 and CXCL12. C: Forces acting on different cell types. Macrophages are subject to mechanical forces due to interactions with nearby cells, and random forces which simulate their exploration of their environment as highly motile cells. Macrophages also experience chemotactic forces that are directed up spatial gradients of CSF-1 and CXCL12, and whose magnitude depends on p. Tumour cells experience mechanical forces due to interactions with neighbouring cells, and chemotactic forces in the direction of increasing EGF. Stromal cells experience mechanical forces due to interactions with neighbouring cells. Necrotic cells experience these interaction forces, which decrease in magnitude as they decrease in size. All cells experience a drag force. D: Summary of the phases of macrophage-mediated tumour cell migration in our ABM. i) M₁ macrophages extravasate from blood vessels in response to CSF-1. ii) M₁ macrophages migrate into the tumour mass in response to CSF-1, where they may kill tumour cells. iii) Exposure to TGF-β causes macrophages to adopt an M₂ phenotype. iv) M₂ macrophages produce EGF, which acts as a chemoattractant for tumour cells. v) M₂ macrophages migrate towards blood vessels, in response to CXCL12 gradients. E: Schematic summarising the sources of CSF-1, TGF-β, EGF and CXCL12 in our model, and their interactions with cells, as described in steps i-v of panel D.