Abstract PR07: The role of keratinocyte desmoglein 1 in shaping the melanoma tumor niche
Authors: Hope E. Burks, Christopher R. Arnette, Jennifer L. Koetsier, Joshua A. Broussard, Valarie Ogwo, Quinn R. Roth-Carter, Pedram Gerami, Jodi L. Johnson, Kathleen J. Green
Journal: Cancer Research (2020)

Abstract Melanoma is an aggressive cancer arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. Keratinocytes and melanocytes communicate through both contact and paracrine signaling, a niche called the pigmentary unit. Ultraviolet (UV) radiation-induced melanocyte mutations drive melanoma formation and progression, but the role of keratinocytes and an altered microenvironment in melanomagenesis is understudied. We showed that the keratinocyte-specific desmosomal cadherin, desmoglein 1 (Dsg1), is reduced in response to acute UV exposure. Here, we show that Dsg1 is progressively reduced in regions surrounding human dysplastic nevi, melanoma in situ, and stage I/II melanomas, preceding loss of E-cadherin that occurs in later stages. Since we previously showed that Dsg1 suppresses EGFR/Erk1/2 signaling and regulates keratinocyte cytokine profiles, we hypothesized that altered keratinocyte Dsg1 expression governs melanocyte behavior and transformation through paracrine signaling. Dsg1 knockdown via shRNA elevated phospho-EGFR, phospho-Stat3, phospho-ERK and nuclear NFκB, accompanied by increases in IL-1α, IL-1β, IL-6, and IL-8, and CXCL1 proinflammatory cytokine mRNAs and secretion of IL6, IL8, and CXCL1. Melanocytes grown in conditioned media from Dsg1-deficient keratinocytes increased MITF transcription, while AXL transcript levels remained unchanged, a signature associated with early-stage melanoma. Consistent with increased MITF, melanocytes cultured in conditioned media from Dsg1-depleted keratinocytes increased pigment secretion, reversible by inhibiting the melanocortin 1 receptor. Melanocytes incorporated into Dsg1-deficient 3D human skin equivalents mis-localized to suprabasal layers, similar to pagetoid behavior in early melanoma. This, combined with the loss of keratinocyte Dsg1 surrounding human melanoma lesions, led us to examine mechanisms of sustained Dsg1 loss in the tumor niche. Keratinocytes cultured in melanoma cell-conditioned media reduced Dsg1 expression, suggesting that Dsg1 downregulation is maintained by melanoma cells post-transformation. We postulate that keratinocyte Dsg1 downregulation may initially be part of the skin’s protective response against UV exposure through its role in increasing pigmentation. However, chronic Dsg1 loss may contribute to melanoma initiation and be important for the maintenance of the promelanoma tumor niche. This abstract is also being presented as Poster A02. Note: This abstract was not presented at the conference. Citation Format: Hope E. Burks, Christopher R. Arnette, Jennifer L. Koetsier, Joshua A. Broussard, Valarie Ogwo, Quinn R. Roth-Carter, Pedram Gerami, Jodi L. Johnson, Kathleen J. Green. The role of keratinocyte desmoglein 1 in shaping the melanoma tumor niche [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR07.