Crosstalk in Skin: Loss of Desmoglein 1 in Keratinocytes Inhibits BRAFV600E-induced Cellular Senescence in Human Melanocytes

Melanoma arises from transformation of melanocytes in the basal layer of the epidermis where they are surrounded by keratinocytes, with which they interact through cell contact and paracrine communication. Although research focuses on how the accumulation of oncogene and tumor suppressor gene mutations in melanocytes drive melanoma development, how alterations in keratinocytes serve as extrinsic drivers of melanoma initiation and progression is poorly understood. We recently identified keratinocyte desmoglein 1 (Dsg1) as an important mediator of keratinocyte:melanoma crosstalk. Here we address the extent to which Dsg1 loss, which occurs in response to acute environmental stress such as ultraviolet radiation, affects early steps in melanomagenesis. RNA-Seq analysis revealed that paracrine signals from Dsg1-deficient keratinocytes mediate a transcriptional switch from a differentiated to undifferentiated cell state in melanocytes expressing BRAFV600E. Of 221 differentially expressed genes in BRAFV600E cells treated with Dsg1-deficient conditioned media (CM), the laminin superfamily member NTN4/Netrin-4, which inhibits senescence in endothelial cells, stood out. Indeed, while BRAFV600E melanocytes treated with Dsg1-deficient CM showed signs of senescence bypass, knockdown of NTN4 reversed these effects. These results suggest that Dsg1 loss in keratinocytes provides an extrinsic signal to push melanocytes towards oncogenic transformation once an initial mutation has been introduced.