Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle

• 成果类型: Article
• 署名作者: Kandyba, Eve; Jabouille, Arnaud; Calvet, Ferriol; Li, Yun Rose; Curtabbi, Andrea; Cristea, Diana; Shin, Joyce; Delrosario, Reyno; Anzules, Jonathan; Wu, Di; Quigley, David; Taylor, Mark; Zanette, Camila; Lo, Fang Yin; Higgins, Jacob; Salk, Jesse; Lopez-Bigas, Nuria; Balmain, Allan
• 署名单位: University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; City of Hope; Translational Genomics Research Institute; Instituto de Salud Carlos III; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Pompeu Fabra University; ICREA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv8291
• 发表日期: 2026-08-06
• 页码: eadv8291
• 关键词: MOUSE SKIN; somatic mutation; transgenic mice; ras; carcinogenesis; promotion; lgr6; PAPILLOMAS; expression; KERATIN

摘要

The identification of the cancer cell of origin is a fundamental issue in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single-cell transcriptomics, and duplex sequencing to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and/or Lrig1+ stem cells of the upper hair follicle but only very rarely from the Lgr5+ and Krt19+ hair follicle bulge. Lgr6+ stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment, resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between the Hras and Kras pathways that influences clonal selection.