Keratinocytes account for 90% of the cells in the outer layer of skin and are among the cell types incipient melanomas interact with most frequently. They play varying roles in the skin cancer. Growth factors they secrete have, for example, long been known to stoke tumor progression. More recently, Ludwig Oxford’s Richard White and his colleagues discovered that desmosome mutations in these nonmalignant cells can drive melanoma cell proliferation. On the other hand, keratinocytes can inhibit cancer initiation by confining transformed melanocytes to the epidermis. In a June issue of eLife, researchers led by Richard and Yilun Ma at the Memorial Sloan Kettering Cancer Center—including Ludwig Harvard’s Tuulia Vallius and Peter Sorger—reported an alternative mechanism by which keratinocytes can restrain the cancer. Employing a zebrafish model to observe the earliest stages of melanoma, they discovered that keratinocytes around melanoma cells undergo an epithelial-to-mesenchymal transition (EMT) reminiscent of their behavior during wound-healing. Overexpressing the EMT-orchestrating transcription factor Twist in keratinocytes improved zebrafish survival, apparently by curtailing melanoma invasion. Single-cell analysis revealed that melanoma cells around those keratinocytes tended to be more differentiated and less invasive. The researchers also identified the molecular interactions between melanoma cells and keratinocytes responsible for this effect. It is noteworthy that EMT—which is typically engaged by invasive cancer cells in tumors—can, in the melanoma microenvironment, inhibit cancer invasion.
Restraint of melanoma progression by cells in the local skin environment
eLife, 2026 June 30