Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma
Cutaneous squamous cell carcinomas (cSCCs) arise from keratinocytes in the skin, but the molecular changes driving this transformation remain unclear. To better understand this process, we perform multi-omic profiling of keratinocytes, actinic keratoses, and cSCCs. Single-cell mutational analyses reveal that most keratinocytes have remarkably low mutation burdens; however, keratinocytes with TP53 or NOTCH1 mutations exhibit substantially higher burdens. These findings suggest that keratinocytes can withstand high dosages of cumulative ultraviolet radiation, but certain pathogenic mutations break these adaptive mechanisms, inducing a mutator phenotype. Mutational profiling of cSCCs adjacent to actinic keratoses reveals TERT promoter and CDKN2A mutations emerge in actinic keratoses, whereas additional mutations that inactivate ARID2 and activate the mitogen-activated protein kinase pathway delineate the transition to cSCC. Surprisingly, actinic keratoses are often not related to their neighboring cSCC. Spatial analyses reveal gene expression heterogeneity, including checkpoint molecule enrichment at invasive fronts, highlighting tumor and immune cell interactions.
Authors
- A. Hunter Shain (ORCID: https://orcid.org/0000-0002-2999-9706)
- Daniel B. Chen
- Harsh Sharma (ORCID: https://orcid.org/0000-0002-9862-6794)
- Sarah T. Arron (ORCID: https://orcid.org/0000-0001-5669-0627)
- Jeffrey B. Cheng (ORCID: https://orcid.org/0000-0001-9821-4549)
- Aravind K. Bandari (ORCID: https://orcid.org/0000-0001-6786-520X)
- Raymond J. Cho (ORCID: https://orcid.org/0000-0001-6090-6603)
- Noel Cruz‐Pacheco (ORCID: https://orcid.org/0000-0001-8989-7093)
- Pedram Gerami (ORCID: https://orcid.org/0000-0002-6194-1037)
- Boris C. Bastian (ORCID: https://orcid.org/0000-0003-1836-6062)
- Christopher D. George (ORCID: https://orcid.org/0000-0003-2790-5443)
- Bishal Tandukar (ORCID: https://orcid.org/0000-0002-9650-1664)
- Delahny Deivendran (ORCID: https://orcid.org/0000-0002-3046-2906)
- Iwei Yeh (ORCID: https://orcid.org/0000-0002-3941-3561)
- Albert Xu (ORCID: https://orcid.org/0000-0001-5938-561X)
- Meng Wang (ORCID: https://orcid.org/0000-0003-3209-1026)
- Drew K. Saylor
- Limin Chen (ORCID: https://orcid.org/0000-0002-7370-6499)
- Annika L. Marty (ORCID: https://orcid.org/0009-0009-0554-131X)
Institutions
- Northwestern University (US)
- University of California, San Francisco (US)
- University of Zurich (CH)
- Erasmus MC (NL)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Case Western Reserve University (US)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41467-025-65687-y
- Primary Topic
- Nonmelanoma Skin Cancer Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Melanoma Research Alliance
- LEO Fondet
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases