Journal Article

DKFZ-2025-02942

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Primary Keratinocyte Model of Actinic Keratosis Reveals UV-Induced DNA Damage Accumulation and Persistent Interferon Signaling.

Elsbroek, L. (First author)DKFZ* ; Reuschlein, K. ; Karsai, S. ; Geueke, A. ; von Petersdorff-Campen, M. ; Bresch, M. ; Steinkraus, V. ; Weisenseel, P. ; Wolf, P. ; Winnefeld, M. ; Lyko, F.DKFZ* ; Kolbe, L.

2026
Elsevier Amsterdam

Abstract: Actinic keratosis (AK) is a precancerous, UV-induced skin lesion that can progress to cutaneous squamous cell carcinoma (cSCC). While UV radiation drives mutations and immunosuppression in the skin, keratinocyte-intrinsic responses to chronic, low-dose solar UV exposure have been insufficiently studied in AK. We established a patient-derived in vitro model using primary keratinocytes from AK lesions and age-matched, sun-exposed skin to investigate how repeated low-dose UV irradiation shapes keratinocyte stress responses. Integrating morphological profiling, cyclobutane pyrimidine dimer (CPD) quantification and bulk RNA sequencing, we observed morphological remodeling and accumulating DNA damage in AK keratinocytes despite activation of DNA repair and unfolded protein response pathways. Transcriptomic analyses revealed constitutive and UV-enhanced interferon signaling in AK cells, including upregulation of innate DNA sensing and ISGylation genes. Meta-analysis of five independent datasets validated interferon pathway activation as a conserved feature of AK, and interferon alpha exposure further sensitized AK keratinocytes to UV-induced CPD accumulation. Immunohistochemistry confirmed lesion-specific enrichment of ISG15 and UBE2L6 in AK epidermis, indicating spatially confined interferon pathway activation in vivo. Our model uncovers sustained interferon signaling and attenuated DNA damage repair as keratinocyte-intrinsic features of AK, suggesting that persistent interferon responses may modulate UV-induced damage responses and contribute to early photocarcinogenesis.

Keyword(s): Actinic keratosis ; DNA damage ; Interferon signaling ; Photocarcinogenesis ; UV stress

Note: DKFZ-ZMBH Alliance / #EA:A130# / Volume 146, Issue 7, July 2026, Pages 1837-1850.e4

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Contributing Institute(s):

1. Epigenetik (A130)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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