Fig. 6: Summary diagram: tumour growth modes impact the extent, spatial features and temporal trajectories of clonal diversification.

Surface growth models lead to attenuated progression with extensive subclonal diversification, reflective of branched evolution. At the early stage, the birth and outgrowth of proliferatively advantageous subclones causes the formation of surface budding structures and consequently a distorted tumour contour. As these subclones grow to collectively constitute the tumour frontier at a later stage, the tumour contour returns to a more circular shape with enrichment of youngest subclones and microdiversity hotspots and enhancement of fitness near the tumour margin. The incorporation of central necrosis causes the loss of macrodiversity but at the same time permits continued subclonal diversification in the tumour interior, evidenced by the enrichment of youngest subclones and microdiversity hotspots. In contrast, volume growth models give rise to dichotomous patterns of tumour growth and clonal evolution, developing tumours that are either indolent with ‘lack of evolution’ or aggressive with early birth of fitter subclone and rapid progression. The distributions of youngest subclones, microdiversity hotspots and fitness in volume growth models are more uniform than those in surface growth models.