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

Abstract

Melanoma arises from transformation of melanocytes in the basal layer of 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 melanomagenesis, 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 mediator of keratinocyte:melanoma crosstalk. In this study, we address the extent to which DSG1 loss, which occurs in response to environmental stress such as UVR, affects early steps in melanomagenesis. RNA-sequencing analysis revealed that paracrine signals from DSG1-deficient keratinocytes mediate a transcriptional switch from a differentiated to undifferentiated cell state in melanocytes expressing BRAF^V600E. Of 221 differentially expressed genes in BRAF^V600E cells treated with conditioned media from DSG1-deficient keratinocytes, the laminin superfamily member Netrin-4 (NTN4), which inhibits senescence, stood out. Indeed, although BRAF^V600E melanocytes treated with conditioned media from DSG1-deficient keratinocytes showed signs of senescence bypass, NTN4 knockdown reversed these effects, whereas ectopic Netrin-4 expression mimicked them. These results suggest that DSG1 loss in keratinocytes provides an extrinsic signal to push melanocytes toward oncogenic transformation once an initial mutation has been introduced.