Project Details
Projekt
From actinic keratosis to invasive squamous cell carcinoma: Impact of AHR and p27KIP1 on malignant transformation
Subject Area
Dermatology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076
The incidence of cutaneous squamous cell carcinomas (SCC) has been increasing steadily for years. The most important risk factor for the development of this malignancy is the chronic exposure to ultraviolet (UV) radiation. The majority of SCC arises from actinic keratosis (AK), a precancerous precursor which predominantly occurs on sun-exposed skin areas. Interestingly, only a small percentage of AK develops into invasive SCC. The underlying molecular mechanisms driving this process of malignant transformation are not well understood. In the context of photocarcinogenesis, we have shown that the aryl hydrocarbon receptor (AHR), a transcription factor, which is activated in epidermal cells by photoproducts of the amino acid tryptophan, regulates DNA damage-dependent responses in UVB-exposed keratinocytes. Specifically, AHR inhibits both DNA repair and apoptosis by modulating the intracellular localization and the protein level of the tumor suppressor p27KIP1 (p27). Studies on extracutaneous cancers revealed that a mislocalization of p27 in the cytoplasm induced migration, invasion and other processes, which contribute to the malignant transformation. Further preliminary data indicate that proinflammatory cytokines inhibit the metabolism of AHR-activating tryptophan photoproducts, thereby amplifying the activation of the AHR-p27 axis. In the current project, we will test the hypothesis that an inflammatory micromilieu fosters the accumulation of AHR agonists and the subsequent activation of the, in this context, oncogenic AHR-p27 axis. As a result, AK cells lose their contact inhibition, enhance their motility and grow invasive, finally leading to their transformation into malignant SCC cells. In order to test our working hypothesis, we will investigate whether 1.) an inhibition of CYP1A enzyme activity by inflammatory mediators, such as TNFα, is sufficient to induce or amplify AHR-dependent signaling pathways in AK cells, 2.) an activation of AHR in the presence of inflammatory mediators results in a cytosolic mislocalization and/or proteolysis of the p27 protein, 3.) an activation of the AHR-p27 axis induces the malignant transformation of AK cells in vitro and in vivo, and 4.) comparative immune-/histological staining and RNAseq analyses (cells, xenograft mouse model, clinical samples) enable us to identify AK-specific prognostic signatures. The overall aim of this research project is to identify and validate the AHR-p27 axis as a molecular target for chemopreventive measures to reduce the transformation rate of premalignant AK.
DFG Programme
Research Units
