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

ABSTRACT: Receptor-interacting protein kinase 4 (RIPK4) has been implicated in the progression of numerous tumours. 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. Despite exhibiting features of a partial shift toward an amoeboid phenotype such as membrane blebbing and increased MLC2 phosphorylation, RIPK4 knockout cells display impaired motility and invasion. Re-expression of RIPK4 restores mesenchymal morphology and migratory capacity. Together, our results establish RIPK4 as a critical regulator of melanoma invasion and metastasis. Nonetheless, they also demonstrate that the loss of RIPK4 function activates compensatory phenotypic shifts in melanoma cells that fail to fully rescue their invasive potential.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314542 | GEO | 2026/04/30

REPOSITORIES: GEO

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Project description:Dissection of melanoma heterogeneity through gene expression profiling has led to the identification of two major phenotypes, conventionally defined as “MITF high / proliferative” and “AXL high / invasive”. Tumors or single melanoma cells characterized by a predominant AXL-related gene program show enhanced expression of sets of genes involved in motility, invasion and regulation of epithelial-mesenchymal transition (EMT), while these genes are downregulated in tumors or cells with a predominant MITF-related gene program. The activation of the AXLhi/MITFlo invasive gene program in melanoma is characterized by aberrant expression of transcription factors (TFs) involved in the embryonic EMT process. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Here we provide evidence for a new actionable pathway that controls melanoma EMT-like/invasive phenotype. We show that in MITFlo melanomas, the TF NFATc2 controls the EMT-like transcriptional program, the invasive ability of neoplastic cells, as well as in-vitro and in-vivo growth, through a pathway that functionally links c-myc to FOXM1 and EZH2. Targeting of NFATc2, FOXM1 or EZH2 inhibited melanoma migratory and invasive activity. Moreover, pharmacological co-targeting of NFATc2 and EZH2 promoted apoptosis of BRAF-mutant melanomas with intrinsic resistance to BRAF inhibition.

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

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