Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1), controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in the surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Slug, and consequently decreases expression of the Dsg1 transcriptional activator Grhl1. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.
Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration
Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. P. Gerami reported personal fees from Castle Biosciences outside the submitted work. No other disclosures were reported.
- Award Id(s): P30 AR075049,R01 CA228196,R01 AR041836,R01 AR043380,T32 CA009560,T32 CA080621-14,T32 CA070085,P30-AR069589
- Award Id(s): P30-CA0605
Hope E. Burks, Jenny L. Pokorny, Jennifer L. Koetsier, Quinn R. Roth-Carter, Christopher R. Arnette, Pedram Gerami, John T. Seykora, Jodi L. Johnson, Ziyou Ren, Kathleen J. Green; Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration. J Cell Biol 6 November 2023; 222 (11): e202212031. doi: https://doi.org/10.1083/jcb.202212031
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