Role of the AHR pathway in UV-induced initiation and progression of melanoma and in resistance to therapy

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Melanoma, the most lethal type of skin cancer, accounts for almost 2% of cancer cases worldwide, with an increasing incidence due to the unbroken trend of recreational UV exposure. The aryl hydrocarbon receptor (AHR), a ligand binding transcription factor of the basic helix-loop-helix Per-ARNT-Sim family, was initially described as the receptor for the dioxin TCDD and has been shown to mediate the detoxification of environmental pollutants. More recently, a multitude of physiological and endogenous ligands have been discovered, along with increasing evidence of physiological roles of AHR in cell proliferation, differentiation and inflammatory responses. UV light has been shown to generate the high affinity AHR agonist FICZ that promotes skin tanning as a protective response against UV. However, in cancer cells AHR activation promotes tumor progression. The current project is based on the hypothesis that AHR signaling promotes protective melanocyte responses to UV irradiation in physiological settings, whereas in pathologic settings, AHR signaling enhances malignant transformation as well as metastatic progression and impairs the efficacy of T cell directed immunotherapies. In the first work package of the project, we will use melanocyte-specific, conditional AHR knockout mice to characterize the impact of AHR signaling on the response of melanocytes to UV light. Additionally, we will also analyze the role of AHR signaling on UV-induced tumor development and progression by utilizing the Hgf-Cdk4 melanoma model crossed with the melanocyte-specific AHR knockout mice. In the second work package, we will assess the role of AHR signaling on immunotherapy. For this, we will use our transplantable melanoma cell line HCmel12 with and without a CRISPR mediated AHR knockout and perform adoptive T-cell transfer. Furthermore, we will also combine adoptive cell transfer therapies with pharmacological AHR inhibition in mice transplanted with HCmel12 melanoma cells to assess the future prospect of therapeutic AHR inhibition in man. In the third work package, we will characterize the AHR signaling dynamics in melanocytes and melanoma cells in vitro. Subsequently, we attempt to analyze the impact of AHR signaling on inflammation-induced melanoma cell plasticity and unravel the underlying molecular mechanism. In the final work package, we will analyze the impact of AHR signaling on the dynamics of melanoma cell transcriptional plasticity in response to inflammatory and therapeutic stimuli via single cell RNA sequencing. Additionally, we will also characterize AHR signaling on the differentiation trajectories of cutaneous melanocytes and melanoma cells following UVB irradiation. We expect that the insights gained from this project will provide a rationale for the future therapeutic modulation of AHR signaling in the treatment of melanoma.