Tissue structure accelerates evolution: premalignant sweeps precede neutral expansion

Recent debate on tumor heterogeneity has largely centered on the presence (or absence) of subclonal selection. While neutral and Darwinian models of tumor evolution have both been shown to recapitulate bulk sequencing data, multi-region sequencing has produced evidence supporting the hypothesis that early Darwinian selection precedes late neutral evolution after malignant transformation. Transitioning modes of evolution (Darwinian to neutral) may be the outcome of cellular architecture dictating spatial constraints for growth. Using a classic, well-studied computational model of tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how tissue structure influences functional (driver) mutations and genetic heterogeneity over time. This novel model extension represents biologically realistic scale (1e6 - 1e7 cells) in a biologically realistic setting (3-dimensional breast ductal network derived from imaging data) of premalignancy. The branching topology of ductal networks at tumor initiation determines two important evolutionary accelerants: spatial constraints and cellular dispersal. This model approach explores a key mechanism behind both inter-patient and intratumoral tumor heterogeneity: competition for space. Initial spatial constraints determine the emergent mode of evolution (Darwinian to neutral) without a change in cell-specific mutation rate or fitness effects.