Sphingolipid paracrine signaling impairs keratinocyte adhesion to promote melanoma invasion

Melanoma is the deadliest form of skin cancer due to its propensity to metastasize. It arises from melanocytes, which are attached to keratinocytes within the basal epidermis. Here, we hypothesize that, in addition to melanocyte-intrinsic modifications, dysregulation of keratinocyte functions could initiate early-stage melanoma cell invasion. We identified the lysolipid sphingosine 1-phosphate (S1P) as a tumor paracrine signal from melanoma cells that modifies the keratinocyte transcriptome and reduces their adhesive properties, leading to tumor invasion. Mechanistically, tumor cell-derived S1P reduced E-cadherin expression in keratinocytes via S1P receptor dependent Snail and Slug activation. All of these effects were blocked by S1P2/3 antagonists. Importantly, we showed that epidermal E-cadherin expression was inversely correlated with the expression of the S1P-producing enzyme in neighboring tumors and the Breslow thickness in patients with early-stage melanoma. These findings support the notion that E-cadherin loss in the epidermis initiates the metastatic cascade in melanoma. [Display omitted] •Primary melanoma cells overexpress sphingosine kinase 1 (SK1), the S1P-producing enzyme•Tumor cell-derived S1P promotes melanoma cell motility in a non-cell-autonomous manner•S1P changes keratinocyte transcriptome and adhesive function through S1P2/3 receptors•Low epidermal E-cadherin and high tumoral SK1 correlate with invasion in primary melanomas Noujarède, Carrié et al. identify sphingosine 1-phosphate (S1P), secreted by melanoma cells, as a paracrine lipid factor that reduces the adhesive properties of keratinocytes and promotes tumor invasion. Low E-cadherin expression in the epidermis, associated with high expression of S1P-producing enzymes in neighboring tumors, support the invasive potential of early-stage melanoma.