Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration

Melanoma cells exist in a bidirectional communication unit with lesional keratinocytes. In this niche, melanoma cells hijack keratinocyte signaling, causing them to produce promigratory chemokines through the downregulation of keratinocyte desmosomal cadherin Dsg1, leading to increased migration in vitro and an associated epidermal spread in vivo. Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1), controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in the surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Slug, and consequently decreases expression of the Dsg1 transcriptional activator Grhl1. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.

Automated summary

Melanoma cells hijack keratinocyte signaling to downregulate Dsg1 expression, leading to increased migration and epidermal spread. Paracrine signaling via CXCL1/CXCR2 and regulation of Slug and Grhl1 are involved in this intercellular communication.