1. Sphingolipid paracrine signaling impairs keratinocyte adhesion to promote melanoma invasion
- Author
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Justine Noujarède, Lorry Carrié, Virginie Garcia, Maxime Grimont, Anaïs Eberhardt, Elodie Mucher, Matthieu Genais, Anne Schreuder, Stéphane Carpentier, Bruno Ségui, Laurence Nieto, Thierry Levade, Susana Puig, Teresa Torres, Josep Malvehy, Olivier Harou, Jonathan Lopez, Stéphane Dalle, Julie Caramel, Laure Gibot, Joëlle Riond, and Nathalie Andrieu-Abadie
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CP: Cancer ,CP: Metabolism ,Biology (General) ,QH301-705.5 - Abstract
Summary: 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.
- Published
- 2023
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