Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRAS Q61K in an Ink4a deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain and liver metastases. Whole genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.

BACKGROUNDFor decades, researchers have strived to analyze the process of tumour formation and progression. Despite the immense accumulation of knowledge, cancer still remains one of the biggest burdens of our society today. According to the WHO, nearly one in six deaths worldwide was attributed to cancer in 2020. Hence, it is crucial to revisit and build upon recent achievements to improve our understanding of this disease.One of the most important concepts to describe the growth and spreading of tumour cells in patients over time is the phenotype-switching model. 1 This model was first discovered in melanoma and is also applicable to other tumours. It is based on the idea that tumour cells can exist in two different cellular states. On the one hand, they exhibit a high proliferative activity with a high rate of glycolysis, but low migrative and invasive capacity. On the other hand, cells can exist in a state hallmarked by up-regulation of migrative and invasive behaviour with inflammation-related pathways being increased. Therefore, increasing evidence supports the idea that tumours progress to metastasis by dynamically switching from a local, proliferative state to a highly migrative state, whichThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.