Selection-driven tumor evolution involving non-cell growth promotion leads to patterns of clonal expansion consistent with neutrality interpretation

Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. As space represents a key growth-limiting ecological resource, the ability to gain and explore this resource is likely to be under strong selection. Using agent-based computational modeling, we explored the consequences of the interplay between phenotypic strategies centered on gaining access to new space through cell-extrinsic degradation of extracellular matrix barriers and the exploitation of this resource through maximizing cell proliferation. While cell proliferation is a cell-intrinsic property, newly accessed space represents a public good, which can benefit both producers and non-producers. We found that that this interplay results in ecological succession, enabling emergence of large, heterogenous, and highly proliferative populations. Even though in our simulations both remodeling and proliferation strategies were under strong positive selection, their interplay led to sub-clonal architecture that could be interpreted as evidence for neutral evolution, warranting cautious interpretation of inferences from sequencing of cancer genomes.