Dangerous liaisons: Loss of keratinocyte control over melanocytes in melanomagenesis

Melanomas arise from transformed melanocytes, positioned at the dermal‐epidermal junction in the basal layer of the epidermis. Melanocytes are completely surrounded by keratinocyte neighbors, with which they communicate through direct contact and paracrine signaling to maintain normal growth control and homeostasis. UV radiation from sunlight reshapes this communication network to drive a protective tanning response. However, repeated rounds of sun exposure result in accumulation of mutations in melanocytes that have been considered as primary drivers of melanoma initiation and progression. It is now clear that mutations in melanocytes are not sufficient to drive tumor formation—the tumor environment plays a critical role. This review focuses on changes in melanocyte‐keratinocyte communication that contribute to melanoma initiation and progression, with a particular focus on recent mechanistic insights that lay a foundation for developing new ways to intercept melanoma development. Bi‐directional communication between keratinocytes and melanocytes is required for UV‐mediated tanning and the process of melanocyte transformation and melanoma development. Here we review recent literature unveiling mechanisms by which signaling between these cells promotes pigmentation, allows BRAF mutant melanocytes to escape senescence, and enables melanoma cells to invade and metastasize.