Genotoxic Stress Determines Cell Fate Decision of Hair Graying or Melanoma

Cellular responses to stressors contribute to aging phenotypes, including hair graying and cancer. In particular, melanocyte stem cells (McSC) are depleted as part of age-associated stem cell exhaustion, which is exacerbated by genotoxic stressors. To determine the mechanisms that govern stress responses, Mohri and colleagues conducted fate tracing of stem cells within the hair follicle niche. Mice treated with ionizing radiation (IR) that induced DNA double-strand breaks demonstrated a p53-dependent senescence phenotype, termed senescence-coupled differentiation, characterized by McSC depletion, hair graying, and increased expression of p21. In contrast, mice treated with carcinogens, including 7,12-dimethylbenz(a)anthracene (DMBA) and ultraviolet B (UVB), showed self-renewal of McSCs and developed melanocytic lesions. To elucidate the mechanisms driving the fate of McSCs introduced to stress, RNA sequencing was conducted after treatment with IR or DMBA. Gene set enrichment analysis revealed upregulation of the p53 pathway with IR treatment and arachidonic acid (AA) metabolism in DMBA-treated McSCs. Mice lacking p53 showed rescue of hair graying, while injection of the AA metabolite PGE2 suppressed this phenotype, supporting the antagonistic effects of DMBA on McSC depletion and hair graying. Analysis of hair follicle stem cells upon DMBA or UVB treatment revealed an upregulation of Kitl, known to play a role in melanocyte development. Kitl knockout mice showed McSC depletion, hair graying, and fewer melanocytic lesions, demonstrating the necessity of KITL for McSC self-renewal. Further, samples from patients with melanoma had higher expression of KITL compared to normal skin. To evaluate the antagonism between hair graying and melanoma, mice with mutant RAS or BRAF, downstream effectors of KITL, were utilized. Expression of mutant RAS or BRAF followed by IR treatment resulted in the rescue of McSC depletion, with mice demonstrating milder hair graying. Conversely, in mice that received IR followed by induction of melanoma, IR protected against lesion formation. Collectively, these data demonstrate that individual McSC fate is dictated by KITL-mediated responses to genotoxic stressors, modulating the antagonistic balance between hair graying and melanoma.Mohri Y, Nie J, Morinaga H, Kato T, Aoto T, Yamanashi T, et al. Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma. Nat Cell Biol 2025;27:1647–59.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.