A novel HIF regulation pathway in human melanoma

Every year around 1,800 people develop malignant melanoma in Austria. Treating this condition is still a major challenge because melanoma often shifts to a metastatic form. Therefore, in this project we focus on the elucidation of new mechanisms that are important for the metastatic process. It is already known that the transcription factor HIF is particularly important for the metastatic spread. HIF stability is regulated within cells by the amount of oxygen and by degrading enzymes. In this project we are interested in investigating new regulatory pathways that control the HIF breakdown in melanoma cells. To do this, we will modulate new signalling processes and measure their impact on HIF stabilization. Additionally, we will also investigate the role of these novel mechanisms in supporting melanoma metastasis. Ultimately, we hope not only to open up new diagnostic possibilities, but also to show new approaches for therapeutic intervention. Within this project we hope to make a contribution to further reduce the risk associated with the development of malignant melanoma in human patients.

Our studies have shown that the loss of NLGN4X plays a crucial role in melanoma progression. While NLGN4X is highly expressed in mature melanocytes, samples from melanoma patients show that the amount is reduced with the progression of melanoma. By restoring NLGN4X expression in late-stage melanoma lines, we observed reduced tumor growth after transplantation into human skin organoids. The use of skin organoids, produced from pluripotent stem cells, for cancer research was documented for the first time in this project. Mechanistically, it was found that suppression of NLGN4X also results in loss of the protein VBP1. The reduction of VBP1 leads to the accumulation of HIF1A, which in turn is important for the migration properties of melanoma. Based on these results, it is proposed that reduced levels of NLGN4X are indicative of a metastatic melanoma phenotype and that loss of NLGN4X represents a novel mechanism for HIF induction. We hope that these findings will help to open up new avenues in the treatment of metastatic melanoma and improve the prognosis for affected patients.