Abstract
Cancer development can be viewed as an evolutionary and ecological process, in which the tumour microenvironment (TME) is likely to play a critical role. Unfortunately, the TME is largely ignored or considered static in most cancer evolution models, and different cancers are often studied in isolation. A general theory of adaptive cancer evolution is lacking. Here we establish a phenotypic and genetic model of cancer evolution in three-dimensional (3D) space with a changing TME. With individual-based simulations, we show how cancer cells adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs, changing TMEs can generate complex 3D dynamics of spatio-temporal heterogeneity involving variable subclonal fitness and mixing, driver mutations with different fitness effects and phylogenetic patterns. Our 3D simulations with changing TMEs capture some of the key morphological characteristics of cancer, including spatio-temporal ball-like and irregular clonal/subclonal population structures. A cycling TME, in particular, is capable of generating more driver mutations and promoting cancer adaptation. We predict that the TME is a major limiting factor of adaptive cancer evolution. Finally, our model can be used to simulate anti-cancer treatment strategies and show how they can be subverted by different resistance mechanisms. Our study provides an evolutionary and ecological framework for understanding cancer development and treatment, and provides novel insights into the processes of adaptive cancer evolution and precision cancer medicine.
