Longevity & AgingScientists Map the Genetic Steps That Turn Skin Cells Into Cancer
Researchers at UCSF performed single-cell mutational profiling, bulk DNA sequencing, and spatial transcriptomics across normal keratinocytes, actinic keratoses, and cutaneous squamous cell carcinomas (cSCCs). They found that most keratinocytes maintain surprisingly low mutation burdens despite heavy UV exposure, but cells harboring TP53 or NOTCH1 mutations show dramatically higher burdens—suggesting these mutations trigger a 'mutator phenotype.' TERT promoter and CDKN2A mutations appear in actinic keratoses, while ARID2 inactivation and MAPK pathway activation mark the transition to invasive cSCC. Strikingly, adjacent actinic keratoses are often genetically unrelated to neighboring cSCCs, challenging the assumption that they share a direct lineage. Spatial analyses also reveal immune checkpoint molecule enrichment at tumor invasive fronts.
