252: Keratinocytes to cSCC: genetic steps

Deivendran D et al., Nature Communications, doi:10.1038/s41467-025-65687-y - Single-cell and spatial multi-omic profiling maps the genetic and transcriptional changes from normal keratinocytes through actinic keratoses to invasive cutaneous squamous cell carcinoma. Key terms: keratinocytes, actinic keratosis, TP53, ARID2, spatial transcriptomics.

Study Highlights:
Single-cell genotyping of 137 keratinocytes revealed most cells have low mutation burdens (median 1.14 mut/Mb) while keratinocytes with TP53 or NOTCH1 mutations carry substantially higher burdens. Deep panel sequencing of 16 paired actinic keratoses and adjacent cSCCs showed TERT promoter and CDKN2A mutations arise in actinic keratoses and additional events such as ARID2 loss and MAPK pathway activation delineate progression to cSCC. Many actinic keratoses were genetically unrelated to their neighboring cSCCs, indicating independent clonal origins despite spatial proximity. Spatial transcriptomics exposed intratumoral heterogeneity and enrichment of immune checkpoint molecules at invasive fronts, implicating localized immune modulation.

Conclusion:
Keratinocyte transformation to cSCC follows a stereotyped sequence where TP53/NOTCH1-associated mutator phenotypes prime cells for acquisition of telomerase activation and cell-cycle defects in precursors, with SWI/SNF disruption and MAPK activation driving invasion alongside spatial immune evasion.

Music:
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Article title:
Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma

First author:
Deivendran D

Journal:
Nature Communications, doi:10.1038/s41467-025-65687-y

DOI:
10.1038/s41467-025-65687-y

Reference:
Deivendran D, Chen L, Tandukar B, Bandari AK, Cruz-Pacheco N, Sharma H, Wang M, Xu A, Chen DB, George CD, Marty AL, Cho RJ, Cheng JB, Saylor D, Gerami P, Yeh I, Arron ST, Bastian BC, Shain AH. Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma. Nature Communications. 2025;16:10663. https://doi.org/10.1038/s41467-025-65687-y

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content for keratinocyte mutational landscape, mutator phenotype, clonal architecture, AK adjacency to cSCC, SWI/SNF (ARID2) disruption, MAPK activation, spatial transcriptomics, immune evasion, and translational implications.
- transcript topics: Keratinocyte mutation burden in normal skin; Mutator phenotype driven by TP53/NOTCH1 mutations; Single-cell clonality and deep sequencing depth; Actinic keratosis to squamous cell carcinoma progression; ARID2 SWI/SNF disruption and MAPK pathway in invasion; Spatial transcriptomics and intratumoral heterogeneity

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Kera...