806 Loss of keratinocyte desmoglein 1 occurs during melanoma development and alters crosstalk between keratinocytes and melanocytes

Abstract

Ultraviolet (UV)-induced mutations in melanocytes are a well-established cause of melanoma. However, histologically normal “fields” of altered keratinocytes present in sun-exposed epidermis could also drive initiation and progression of melanoma. Supporting this idea, we observed reduced expression of the keratinocyte desmosomal cadherin, desmoglein 1 (Dsg1) (which we previously showed is lost in response to UV) in regions surrounding human in situ and stage I/II melanomas. Loss of Dsg1 was specific as expression of E-cadherin was not significantly altered in early tumors. Dsg1-deficient keratinocytes also exhibited indications of impaired Dsg1-dependent signaling including increased phospho-EGFR and nuclear NFκB. To directly determine whether Dsg1 loss affects melanocyte behavior, we carried out in vitro analyses of Dsg1-silenced keratinocytes. Dsg1 knockdown increased keratinocyte expression of mRNAs encoding multiple pro-inflammatory cytokines, which also occurred in primary human melanocytes co-cultured with these keratinocytes. Growth of melanocytes in media conditioned by Dsg1-deficient keratinocytes resulted in significantly increased average melanocyte dendrite length (104μm vs. 74μm in controls; p=0.002) and dendrite number (3.3 vs. 2.6/cell; p=0.001). Melanocytes incorporated into Dsg1-deficient 3D human skin equivalents exhibited aberrant behavior, including increased numbers and mis-localization to suprabasal layers. Based on these observations, we propose that under homeostatic conditions Dsg1 keeps cytokine signaling in check but that Dsg1 loss due to environmental stress disrupts keratinocyte:melanocyte communication through altered paracrine signaling to promote melanoma initiation and/or progression. We propose Dsg1 loss as a potential biomarker for increased melanoma risk and a therapeutic target for histone deacetylase inhibitors, which we have shown increase Dsg1 expression.