Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an epithelial-mesenchymal transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT-transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell-cell interactions.
Journal article
2026-06-01T00:00:00+00:00
13
Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, United States.
Cell Line, Tumor, Keratinocytes, Skin, Animals, Zebrafish, Humans, Melanoma, Skin Neoplasms, Disease Models, Animal, Disease Progression, Coculture Techniques, Epithelial-Mesenchymal Transition, Tumor Microenvironment, Twist-Related Protein 1