While deregulated intracellular signaling initiates melanoma, intercellular crosstalk within the tumor microenvironment, often coordinated by soluble factors, is essential for melanoma progression and metastasis. One such secreted matricellular protein, cellular communication network factor 4 (CCN4), stimulates metastasis in other malignancies. Here, we report that CCN4 expression is associated progressively with reduced overall survival in patients with primary melanomas. To reveal the roles

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... CCN4 in melanoma progression, we used mouse melanoma models and knocked out Ccn4 using a homology-directed repair CRISPR/CAS9 system to generate pools of Ccn4-knockout cells. In vitro assays supported previous findings using clones generated using a double nickase-based CRISPR/CAS9 system that CCN4 promoted an epithelial - mesenchymal-like transition in melanoma cells and stimulated invasion and metastasis. We also found that, while Ccn4 knockout enhanced cell growth in optimal 2D culture conditions, the knockout suppressed certain cell survival signaling pathways and rendered cells less resistant to stress conditions. Tumor cell growth assays at sub-optimal conditions in vitro, quantitative analysis of tumor growth assays in vivo, and transcriptomics analysis of human melanoma cell lines suggested that CCN4 repressed cell growth and simultaneously enhanced cell survival. The collective role of CCN4 suggests a potential therapeutic target for limiting metastatic invasion in melanoma and a biomarker for metastatic potential.