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Updated: May 9, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway
Axelle Wilmerding1, Aurélie Richard2, Nicolas Macagno3,4
1Aix-Marseille University, CNRS, IBDM, UMR 7288, Marseille, France.
Abstract:
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 in vivo model, we discovered that RIPOR2 is a positive transcriptional target of this pathway, including in melanocyte precursors. Similar transcriptional control of RIPOR2 by RAS/ERK is conserved in human melanoma cells. RIPOR2 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.
Insights
RAS/ERK pathway overactivation drives melanoma by upregulating RIPOR2, a gene promoting multinucleation. This finding offers a potential therapeutic target for melanoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Multinucleation in cancer is linked to aneuploidy and tumor aggressiveness.
- Melanoma, characterized by melanocyte overproliferation, involves RAS/ERK pathway hyperactivation.
Purpose of the Study:
- To investigate the role of RAS/ERK pathway targets in melanoma development.
- To identify novel therapeutic targets for melanoma.
Main Methods:
- Single-nucleus RNA sequencing in a chicken embryo model with RAS/ERK pathway overactivation.
- Analysis of RIPOR2 expression and function in human melanoma cells and an animal model.
Main Results:
- RIPOR2 was identified as a positive transcriptional target of the RAS/ERK pathway, conserved in human melanoma.
- Ectopic RIPOR2 expression in human melanoma promotes multinucleation.
- RIPOR2 functions as an atypical RHOA inhibitory protein.
Conclusions:
- RIPOR2, upregulated by RAS/ERK signaling, contributes to melanoma pathogenesis by inducing multinucleation.
- RIPOR2 represents a potential therapeutic target for melanoma.
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