Dangerous liaisons: Loss of keratinocyte control over melanocytes in melanomagenesis

Abstract

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.

Keywords: Melanoma; cadherin; pigmentation; tumor microenvironment; ultraviolet radiation.

FIGURE 1

Keratinocytes regulate the epidermal microenvironment and melanocyte behavior. Keratinocytes and melanocytes in the skin communicate with each other through both direct contact and paracrine signaling. In a normal epidermal microenvironment, both classical cadherins (orange) and desmosomal cadherins (green) are expressed at cellular junctions. In a Dsg1 ‐deficient keratinocyte microenvironment, reduction in the expression of keratinocyte Dsg1 initiates a signaling cascade that alters the production of paracrine factors including IL‐6, IL‐8, and POMC that affects the signaling, morphology, pigment secretion, and localization of neighboring melanocytes. Similarly in a UV‐exposed epidermal microenvironment, UV downregulates keratinocyte Dsg1 (light green) triggering paracrine signaling that affects morphology, pigment secretion, and localization of neighboring melanocytes.

FIGURE 2

Bi‐directional crosstalk between BRAF^V600E mutant melanocytes and keratinocytes regulates melanoma growth. (A) Tagore et al. found that melanocytes synthesize and secrete GABA (purple) to adjacent keratinocytes. In keratinocytes, GABA activates signaling and causes a cell hyperpolarization effect, leading to MYCN activation (black). MYCN promotes the transcription of LIF (light blue), which is then secreted by keratinocytes to regulate melanocyte proliferation. (B) Tong et al. demonstrated the role of Dsg1 in keratinocyte:melanocyte communication and melanomagenesis indicating the loss of Dsg1 in keratinocytes alters adjacent melanocytes through paracrine signaling, thus promoting cellular senescence bypass (dotted arrow) leading to progression to melanoma. (C) Burks et al. showcases in late stage melanoma that paracrine factors (yellow) secreted from melanocytes activate keratinocyte Slug (pink), which in turn inhibits Grhl1 (light green), a transcriptional activator of Dsg1. The consequent loss of Dsg1 activates ERK1/2 (purple) to increase KC CXCL1 production (light orange), which in turn promotes melanocyte migration and melanoma progression through activation of CXCR2 (dark orange). LIF, leukemia inhibitory factor.

FIGURE 3

Loss of Dsg1 in keratinocytes potentially pushes melanocytes along an oncogenic trajectory towards melanoma progression and invasion. (Top) Melanocytes can transform into melanoma through a series of progressive changes triggered by genetic mutations and UV exposure. Initially, UV radiation causes DNA damage in melanocytes, leading to mutations in genes like BRAF and TP53. These changes can result in the formation of benign moles (nevi), which are clusters of proliferating melanocytes. Over time, additional signaling from the niche can drive these cells into the radial growth phase of melanoma, characterized by horizontal spread within the epidermis. As the disease progresses to the vertical growth phase, melanocytes invade deeper into the dermis, increasing the likelihood of metastasis. In this final stage, melanocytes spread through the bloodstream or lymphatic system to other organs, forming secondary tumors and making the cancer more difficult to treat. (Bottom) The signals that regulate this progression from melanoma to invasive melanoma are poorly understood, indicated by the red dashed arrow and box. It has been shown that BRAF^V600E melanocytes are able to bypass senescence potentially due to temporary loss of Dsg1 in KCs which leads to increased motility and reduced differentiation in adjacent melanocytes.