Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones

Clonal fitness and plasticity drive cancer heterogeneity. We used expressed lentiviral-based cellular barcodes combined with single-cell RNA sequencing to associate single-cell profiles with in vivo clonal growth. This generated a significant resource of growth measurements from over 20,000 single-cell-derived clones in 110 xenografts from 26 patient-derived breast cancer xenograft models. 167,375 single-cell RNA profiles were obtained from 5 models and revealed that rare propagating clones display a highly conserved model-specific differentiation program with reproducible regeneration of the entire transcriptomic landscape of the original xenograft. In 2 models of basal breast cancer, propagating clones demonstrated remarkable transcriptional plasticity at single-cell resolution. Dichotomous cell populations with different clonal growth properties, signaling pathways, and metabolic programs were characterized. By directly linking clonal growth with single-cell transcriptomes, these findings provide a profound understanding of clonal fitness and plasticity with implications for cancer biology and therapy.