The ability of Dsg1 to regulate keratinocyte cytokine expression prompted us to explore its role in paracrine signaling in the epidermis. We characterized cytokine expression and secreted factors in Dsg1-deficient keratinocytes and noted overlap with those produced by keratinocytes in response to ultraviolet (UV) irradiation. In addition, Dsg1, but not other cadherins, was reduced in UV-irradiated keratinocytes and organotypic cultures. Thus, we hypothesized that UV-dependent loss of Dsg1 contributes to alterations in keratinocyte cytokine expression that mediate the tanning response.
Indeed, conditioned media from Dsg1-deficient keratinocyte elicited alterations in melanocytes that resemble the tanning response including increased dendricity, elevated pigment secretion, and expression of a transcription factor important for pigment production and melanoma cancer (Fig 1). In the context of 3D organotypic cultures, normal melanocytes surrounded by Dsg1-deficient keratinocytes also exhibited changes in dendricity, pigmentation and altered their localization superficially and increased cell number, akin to transformed cells (Fig 2 below). Interestingly Dsg1 was dramatically reduced in early melanoma lesions. This reduction was first observed in atypical pigmented lesions prior to a melanoma diagnosis, raising the possibility that loss of Dsg1 in nest surrounding pigmented lesions may contribute to melanoma development through elevated paracrine signaling (Fig 3 below).
Future Objectives: We are examining the mechanisms by which Dsg1 regulates keratinocyte: melanocyte cross talk both in vitro, in an animal model resembling human melanoma, and in human tissues. Human patient specimens are being interrogated though laser capture microdissection and transcriptomic analysis of adjacent keratinocyte and melanocyte/melanoma cell to map the evolution of alterations associated with Dsg1 loss. We are collaborating with experts in keratinocyte-melanocyte interactions and melanoma on these projects including Pedram Gerami and Caroline LePoole from Northwestern as well as outside collaborators Zalfa Abdel-Malek and Sancy Leachman.