Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale

Abstract

Intratumour heterogeneity complicates biomarker discovery and treatment personalization, and pervasive cancer evolution is a key mechanism leading to therapy failure and patient death. Thus, understanding subclonal heterogeneity architectures and cancer evolution processes is critical for the development of effective therapeutic approaches which can control or thwart cancer evolutionary plasticity. Current insights into heterogeneity are mainly limited to the macroheterogeneity level, established by cancer subclones that have undergone significant clonal expansion. Novel single cell sequencing and blood-based subclonal tracking technologies are enabling detailed insights into microheterogeneity and the dynamics of clonal evolution. We assess how this starts to delineate the rules governing cancer evolution and novel angles for more effective therapeutic intervention.

Figure 1

Macro and microheterogeneity in cancer evolution. (a) Schematic illustrating clonal evolution. Multiple subclones evolve from the founding clone (blue) and undergo major clonal expansions, changing the composition of the tumour cell population. Subclones are detectable as macroheterogeneity by standard next generation sequencing approaches owing to their large population sizes. Magnifications of small proportions of the cancer cell population (insets) show the population structure at the microheterogeneity level. Newly generated mutations in single cells, which subsequently expand into small subclonal populations are below the detection limit of standard next-generation sequencing techniques and can only be detected through single cell or ultra-deep sequencing technologies. (b) Phylogenetic tree reconstructed from the macroheterogeneity data, depicting a branched evolutionary trajectory. The founding clone (blue) represents the trunk of the phylogenetic tree.

Figure 2

Influence of the fitness landscape on cancer evolutionary patterns. (a) Hypothetical cancer fitness landscape in which the founding cell (red dot) is already located at a fitness peak. Further evolutionary adaptation is only possible through a change in the fitness landscape, for example through a change in the environment or through drug therapy. Microheterogeneity can be extensive in this tumour but macroheterogeneity is absent. (b) Hypothetical fitness landscape where the founding cell is not located at a fitness peak. Tumour subclones can increase their relative fitness through the acquisition of further driver mutations which will lead to subclonal expansion. Increases in fitness are illustrated as arrows climbing up the fitness peaks. If multiple subclones acquire drivers that increase their relative fitness, branched evolution can occur. Multiple fitness peaks indicate multiple possible phenotypes which lead to increased cellular fitness.