Abstract
Interaction between the tumor microenvironment and cancer cell plasticity drives intratumor phenotypic heterogeneity and underpins disease progression and nongenetic therapy resistance. Phenotype-specific expression of the AXL receptor tyrosine kinase is a pivotal player in dormancy, invasion, and resistance to treatment. However, although the AXL ligand GAS6 is present within tumors, how AXL is activated in metastasizing cells remains unclear. Here, using melanoma as a model, we reveal that AXL is activated by exposure to human adipocytes and to oleic acid, a monounsaturated fatty acid abundant in lymph and in adipocytes. AXL activation triggers SRC-dependent formation and nuclear translocation of a β-catenin-CAV1 complex required for melanoma invasiveness. Remarkably, only undifferentiated AXLHigh melanoma cells engage in symbiosis with human adipocytes, in part by triggering WNT5a-mediated lipolysis, leading to AXL-dependent, but FATP-independent, fatty acid uptake and nuclear localization of the β-catenin-CAV1 complex. Significantly, human melanomas in the vicinity of adipocytes exhibit high levels of nuclear CAV1. The results unveil an AXL- and CAV1-dependent mechanism through which a nutritional input drives phenotype-specific activation of a prometastasis program. Given the key role of AXL in a broad range of cancers, the results offer major insights into the mechanisms of cancer cell dormancy and therapy resistance.