Figure 7.

Fitness landscape model

Tumor stem cell phenotype can be represented as a fitness landscape model, where Lgr5+ve CBC and Lgr5−ve RSC represent distinct but interlinked fitness peaks situated along a phenotypic axis. (A) Epithelial cells “climb” these fitness peaks (arrows) through the combination of acquired epithelial mutations and the influence of microenvironmental signaling, placing them at distinct points within the fitness landscape. Bulk transcriptome data can be used to calculate the stem cell index, which reflects stem cell population admixture and can be used as a measure of individual tumor position within this phenotypic axis (boxes). (B) Application of a selective pressure to a fitness peak (e.g Lgr5+ CBC ablation) alters the morphogenic signaling landscape and shifts the stem cell equilibrium toward an alternative phenotype at day 1. Rapid regeneration of the lost CBC population restores the stem cell equilibrium after 5 days. These dynamic shifts can be measured by change in the stem cell index (boxes). Key: green dots, CBC cells; red dots, RSC cells; yellow dots, both marker-expressing cells; gray dots, no stem cell-marker-expressing cells.