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@ARTICLE{Elsbroek:307249,
      author       = {L. Elsbroek$^*$ and K. Reuschlein and S. Karsai and A.
                      Geueke and M. von Petersdorff-Campen and M. Bresch and V.
                      Steinkraus and P. Weisenseel and P. Wolf and M. Winnefeld
                      and F. Lyko$^*$ and L. Kolbe},
      title        = {{P}rimary {K}eratinocyte {M}odel of {A}ctinic {K}eratosis
                      {R}eveals {UV}-{I}nduced {DNA} {D}amage {A}ccumulation and
                      {P}ersistent {I}nterferon {S}ignaling.},
      journal      = {The journal of investigative dermatology},
      volume       = {nn},
      issn         = {0022-202X},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-02942},
      pages        = {nn},
      year         = {2025},
      note         = {DKFZ-ZMBH Alliance / #EA:A130# / epub},
      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.},
      keywords     = {Actinic keratosis (Other) / DNA damage (Other) / Interferon
                      signaling (Other) / Photocarcinogenesis (Other) / UV stress
                      (Other)},
      cin          = {A130},
      ddc          = {610},
      cid          = {I:(DE-He78)A130-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41389957},
      doi          = {10.1016/j.jid.2025.11.018},
      url          = {https://inrepo02.dkfz.de/record/307249},
}