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In neoplastic diseases, the AHR has been described to modulate proliferation and differentiation in dichotomous ways, either inhibiting or augmenting the growth of tumors. The precise role of AHR in melanoma is mostly unknown. Here, we report a functional effect of AHR activation on inflammation\u2010induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of \u201cThe Cancer Genome Atlas\u201d human melanoma cohort, we detected a correlation between AHR expression levels and a dedifferentiated melanoma cell phenotype with an invasive gene signature, which we were able to functionally recapitulate in a panel of human melanoma cell lines. Both human and mouse melanoma cell lines upregulated AHR expression after inflammatory stimulation with tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2\u2010b)carbazole (FICZ) promoted inflammation\u2010induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR\/Cas9\u2010mediated disruption of the AHR gene showed impaired in vivo tumor growth after transplantation in the skin as well as decreased numbers of spontaneous lung metastases. Taken together, our results demonstrate a functional role for AHR expression in melanoma development and metastatic progression. This provides a scientific basis for future experiments that further dissect the underlying molecular mechanisms and assess the potential for AHR inhibition as part of multimodal melanoma treatment strategies.<\/jats:p>","DOI":"10.1002\/ijc.33252","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T21:53:05Z","timestamp":1597355585000},"page":"2902-2913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The aryl hydrocarbon receptor promotes inflammation\u2010induced dedifferentiation and systemic metastatic spread of melanoma cells"],"prefix":"10.1002","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1651-7114","authenticated-orcid":false,"given":"Miriam","family":"Mengoni","sequence":"first","affiliation":[{"name":"Laboratory for Experimental Dermatology, Department of Dermatology University Hospital Magdeburg  Magdeburg 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