Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma

Bishal Tandukar, Delahny Deivendran, Limin Chen, Aravind K. Bandari, Noel Cruz-Pacheco, Harsh Sharma, Meng Wang, Albert Xu, Daniel B. Chen, Christopher D. George, Annika L. Marty, Raymond J. Cho, Jeffrey B. Cheng, Drew Saylor, Pedram Gerami, Iwei Yeh, Sarah T. Arron, Boris C. Bastian and A. Hunter Shain ()
Additional contact information
Bishal Tandukar: University of California San Francisco, Department of Dermatology
Delahny Deivendran: University of California San Francisco, Department of Dermatology
Limin Chen: University of California San Francisco, Department of Dermatology
Aravind K. Bandari: University of California San Francisco, Department of Dermatology
Noel Cruz-Pacheco: University of California San Francisco, Department of Dermatology
Harsh Sharma: University of California San Francisco, Department of Dermatology
Meng Wang: University of California San Francisco, Department of Dermatology
Albert Xu: University of California San Francisco, Department of Dermatology
Daniel B. Chen: University of California San Francisco, Department of Dermatology
Christopher D. George: Erasmus MC, Department of Dermatology
Annika L. Marty: University of California San Francisco, Department of Dermatology
Raymond J. Cho: University of California San Francisco, Department of Dermatology
Jeffrey B. Cheng: University of California San Francisco, Department of Dermatology
Drew Saylor: University of California San Francisco, Department of Dermatology
Pedram Gerami: Northwestern University, Department of Dermatology, Feinberg School of Medicine
Iwei Yeh: University of California San Francisco, Department of Dermatology
Sarah T. Arron: Peninsula Dermatology
Boris C. Bastian: University of California San Francisco, Department of Dermatology
A. Hunter Shain: University of California San Francisco, Department of Dermatology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65687-y

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