Impaired RIPK4 function interferes with the metastatic potential of melanoma cells through deregulation of their adhesive status

In non-melanoma skin cancer, RIPK4 plays a suppressor role, whereas in melanoma it functions as an oncogene that modulates key signalling pathways involved in melanoma cell survival and expansion. Increased RIPK4 levels in metastatic melanoma biopsies prompted us to investigate the consequences of RIPK4 loss for the invasive and metastatic phenotype of melanoma cells.

Using an integrated approach involving clinical samples, in vivo xenograft models, and transcriptomic and 3D functional assays, we show that RIPK4 deletion significantly reduces pulmonary metastasis formation. This reflects its role in late-stage metastatic events, such as extravasation and colonization, particularly since this phenotype correlates with extensive transcriptional reprogramming of adhesion- and motility-related genes in melanoma cells, as evidenced by next-generation sequencing and functional validation in spheroid and collagen-based models.