Studying in vivo cancer cell plasticity, which is linked to resisting cancer therapy, is challenging. Taylor, Kandyba et al. utilized gene expression analysis of autochthonous skin cancer mouse models with controlled complex genetic heterogeneity to monitor stem cell states during skin carcinogenesis.

Next, the authors generated single-cell RNA sequencing (scRNA-seq) data from NSk, papilloma (precancer) and carcinoma cells that were enriched for Lgr6+ cells to track individual metagenes in single cells. Lgr6 expression was identified in the upper hair follicle and in the interfollicular epithelium, whereas the Lgr6 NSk metagene network was found in differentiated keratinocytes, consistent with a role of Lgr6+ cells in repopulating these skin regions during homeostasis and wound healing. Conversely, the Lgr6+ carcinoma metagene was highly expressed in the carcinoma parenchyma, indicating the switch from normal homeostasis to malignancy. While individual stem cell markers separated single cell populations, metagene expression of multiple stem cell markers converged in single cells, and identified a population indicative of lineage plasticity and wound healing (termed plasticity program). Interestingly, stem cells that lacked these metagene networks were detected and these displayed a mutually exclusive program reminiscent of proliferation (termed proliferation program).