For cancer, we develop a 2-D agent-based continuous-space game-theoretical model that considers cancer cells’ proximity to a blood vessel. Based on castrate resistant metastatic prostate cancer (mCRPC), the model considers the density and frequency (eco-evolutionary) dynamics of three cancer cell types: those that require exogenous testosterone (T ⁺ ), those producing testosterone (TP), and those independent of testosterone (T ⁻ ). We model proximity to a blood vessel by imagining four zones around the vessel. Zone 0 is the blood vessel. As rings, zones 1–3 are successively farther from the blood vessel and have successively lower carrying capacities. Zone 4 represents the space too far from the blood vessel and too poor in nutrients for cancer cell proliferation. Within the other three zones that are closer to the blood vessel, the cells’ proliferation probabilities are determined by zone-specific payoff matrices. We analyzed how zone width, dispersal, interactions across zone boundaries, and blood vessel dynamics influence the eco-evolutionary dynamics of cell types within zones and across the entire cancer cell population. At equilibrium, zone 3’s composition deviates from its evolutionary stable strategy (ESS) towards that of zone 2. Zone 2 sees deviations from its ESS because of dispersal from zones 1 and 3; however, its composition begins to resemble zone 1’s more so than zone 3’s. Frequency-dependent interactions between cells across zone boundaries have little effect on zone 2’s and zone 3’s composition but have decisive effects on zone 1. The composition of zone 1 diverges dramatically from both its own ESS, but also that of zone 2. That is because T ⁺ cells (highest frequency in zone 1) benefit from interacting with TP cells (highest frequency in zone 2). Zone 1 T ⁺ cells interacting with cells in zone 2 experience a higher likelihood of encountering a T ^P cell than when restricted to their own zone. As expected, increasing the width of zones decreases these impacts of cross-boundary dispersal and interactions. Increasing zone widths increases the persistence likelihood of the cancer subpopulation in the face of blood vessel dynamics, where the vessel may die or become occluded resulting in the “birth” of another blood vessel elsewhere in the space. With small zone widths, the cancer cell subpopulations cannot persist. With large zone widths, blood vessel dynamics create cancer cell subpopulations that resemble the ESS of zone 3 as the larger area of zone 3 and its contribution to cells within the necrotic zone 4 mean that zones 3 and 4 provide the likeliest colonizers for the new blood vessel. In conclusion, our model provides an alternative modeling approach for considering density-dependent, frequency-dependent, and dispersal dynamics into cancer models with spatial gradients around blood vessels. Additionally, our model can consider the occurrence of circulating tumor cells (cells that disperse into the blood vessel from zone 1) and the presence of live cancer cells within the necrotic regions of a tumor.

Metastatic prostate cancer is initially treated with androgen deprivation therapy (ADT). However, resistance typically develops in about 1 year – a clinical condition termed metastatic castrate-resistant prostate cancer (mCRPC). We develop and investigate a spatial game (agent based continuous space) of mCRPC that considers three distinct cancer cell types: (1) those dependent on exogenous testosterone (T⁺), (2) those with increased CYP17A expression that produce testosterone and provide it to the environment as a public good (T^P), and (3) those independent of testosterone (T⁻). The interactions within and between cancer cell types can be represented by a 3 × 3 matrix. Based on the known biology of this cancer there are 22 potential matrices that give roughly three major outcomes depending upon the absence (good prognosis), near absence or high frequency (poor prognosis) of T⁻ cells at the evolutionarily stable strategy (ESS). When just two cell types coexist the spatial game faithfully reproduces the ESS of the corresponding matrix game. With three cell types divergences occur, in some cases just two strategies coexist in the spatial game even as a non-spatial matrix game supports all three. Discrepancies between the spatial game and non-spatial ESS happen because different cell types become more or less clumped in the spatial game – leading to non-random assortative interactions between cell types. Three key spatial scales influence the distribution and abundance of cell types in the spatial game: i. Increasing the radius at which cells interact with each other can lead to higher clumping of each type, ii. Increasing the radius at which cells experience limits to population growth can cause densely packed tumor clusters in space, iii. Increasing the dispersal radius of daughter cells promotes increased mixing of cell types. To our knowledge the effects of these spatial scales on eco-evolutionary dynamics have not been explored in cancer models. The fact that cancer interactions are spatially explicit and that our spatial game of mCRPC provides in general different outcomes than the non-spatial game might suggest that non-spatial models are insufficient for capturing key elements of tumorigenesis.