Chemically Induced Skin Tumors Arise from Upper Hair Follicle Stem Cells

Pinpointing the cell of origin for a specific tumor type represents an important but often challenging goal in the study of cancer biology. Although genetically engineered mouse models have shown that skin tumors can arise from multiple cell types, these models are not suitable for identifying which cells are naturally targeted by environmental mutagens. In a recent study, Kandyba and colleagues identified the true cell of origin of chemically induced skin tumors, uncovering where and how these cells arise, persist, and respond to tumor promotion. Through fluorescent lineage tracing in mouse models, the authors labeled four skin stem cell populations before exposure to the two-step carcinogenesis protocol comprising of dimethylbenzanthracene and 12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA). Tumors arising from upper hair follicle stem cells, marked by Lgr6 and Lrig1, accounted for the majority of papillomas, while bulge stem cells, previously implicated as the source of skin tumor initiation, rarely gave rise to tumors. Knockdown of Lgr6 reduced papilloma formation and malignant progression, confirming a functional role for Lgr6-positive stem cells. Single-cell RNA sequencing analysis revealed that upper hair follicle stem cells selectively express Cyp1b1, the enzyme required to metabolize DMBA into its mutagenic form. This susceptibility was also observed with a direct-acting mutagen, indicating that the heightened vulnerability of these stem cells is not specific to DMBA metabolism and instead reflects an intrinsic property of the cells. Notably, Lgr6-positive cells harboring the chemically induced driver mutation HrasQ61L remained dormant for up to a year before rapidly generating tumors following tumor promoter exposure. Additionally, tumor promotion was observed to drive competition between oncogenic clones: Spontaneously arising Kras-mutant clones initially expanded but were eliminated by competing Hras-mutant cells. When Hras was genetically deleted, however, Kras-mutant clones persisted and progressed to carcinoma. Together, these findings reposition stem cells within the upper hair follicle as the cell of origin for chemically induced skin cancer and reveal that competition between mutant cell populations can determine which clones progress to malignancy, a dynamic that might inform future cancer prevention strategies.Kandyba E, Jabouille A, Calvet F, Li YR, Curtabbi A, Cristea D, et al. Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle. Science 2026 June 11 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.