The aryl hydrocarbon receptor promotes inflammation‐induced dedifferentiation and systemic metastatic spread of melanoma cells

The aryl hydrocarbon receptor (AHR) is a ligand binding‐transcription factor of the basic helix‐loop‐helix family regulating multiple cellular functions such as differentiation, cell cycle, apoptosis, and inflammatory reactions. 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‐induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of “The Cancer Genome Atlas” 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‐α (TNF‐α). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2‐b)carbazole (FICZ) promoted inflammation‐induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR/Cas9‐mediated 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. What's new? The aryl hydrocarbon receptor (AHR) has important functions in mediating xenobiotic metabolism and in regulating numerous enzymes and transcriptional programs in cells. AHR also is expressed in melanoma and its knockdown has been shown to inhibit tumor cell growth. In our study, the AHR was found to promote inflammation‐induced dedifferentiation of both human and mouse melanoma cells in vitro. In syngeneic immunocompetent mice, AHR expression promoted metastatic dissemination of transplanted melanoma cells. The findings support emerging evidence that the AHR functionally participates in melanoma pathogenesis and provide a rationale to further investigate the AHR as a putative therape