Cancer spatial evolution in a changing microenvironment

Cancer development as an ecological and evolutionary process is poorly understood, which includes early cancer evolution, malignancy and metastasis. It was hypothesised that the tumour microenvironment (TME) plays a critical role in this process. Unfortunately, in most cancer modelling studies the TME is ignored or considered static and different cancers are often studied in isolation. There is a lack of a general theory of cancer adaptive evolution (CAE). Here I establish a genetic and phenotypic model of cancer three-dimensional (3D) spatial evolution in a changing TME. With 3D individual-based simulations I show how cancer cells adapt to diverse changing TME conditions and selection intensities. I am able to capture key histological characteristics of various cancer forms including complex dynamics of spatial-temporal heterogeneity of subclonal fitness and subclonal mixing, ball-like and non-ball-like subclonal structures. Moreover, I identify key evolutionary and phylogenetic patterns of CAE under various combinations of phenotypic, genetic, population genetic and changing TME conditions. I show classical drivers, mini drivers, Darwinian and neutral/nearly neutral evolution and cost of complexity. I demonstrate the importance of ecology in CAE. I show that there are fundamental differences in the mode of CAE when the TME is changing, which is the limiting factor of CAE. Finally, I discuss important implications for cancer evolution theories and cancer personalised medicine.