RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway

Multinucleation in cancer has been shown to promote aneuploidy, which correlates with tumor aggressiveness. This is particularly true for melanoma, a cancer caused by excessive proliferation of melanocytes, whose RAS/ERK pathway is overactivated. Using single-nucleus RNA sequencing after overactivation of the RAS/ERK pathway in the chicken embryo as an <i>in vivo</i> model, we discovered that <i>RIPOR2</i> is a positive transcriptional target of this pathway, including in melanocyte precursors. Similar transcriptional control of <i>RIPOR2</i> by RAS/ERK is conserved in human melanoma cells. <i>RIPOR2</i> emerged as an attractive target because it encodes an atypical RHOA inhibitory protein involved in the development of physiologically multinucleated cell types. We found that RIPOR2 is ectopically expressed in human melanoma and functionally promotes multinucleation in both an animal model and human tumor-derived cells, including melanoma cell lines. Our results suggest that RIPOR2 expression, downstream of RAS/ERK overactivation, may contribute to melanocyte transformation by promoting multinucleation.