Cancer progression and non-genetic therapy resistance are driven by interactions between the tumour microenvironment and cancer cell plasticity. Phenotype-specific expression of the AXL receptor tyrosine kinase is key in cancer invasion and resistance to treatment, but how the ALX is activated has remained unclear.
Using melanoma as a model, the Goding research group and collaborators at University Rey Juan Carlos show that AXL is activated by exposure to human adipocytes and to oleic acid, a fatty acid abundant in lymph and adipocytes. The activation of AXL triggers formation and translocation of a β-catenin-CAV1 complex required for melanoma invasiveness.
Of particular note, only undifferentiated, high in AXL melanoma cells engage in symbiosis with human adipocytes, leading to AXL-dependent fatty acid uptake and nuclear localisation of the β-catenin-CAV1 complex. These results demonstrate an AXL and CAV-1 dependent mechanism by which a nutritional input drives phenotype-specific activation of a pro-metastasis program.
Given the key role of AXL in a wide range of cancers, the results offer major insights into the mechanisms of cancer cell dormancy and therapy resistance.
Professor Colin Goding, Professor of Oncology at Ludwig Cancer Research, said: ‘In melanoma, and many other cancers, cancer cells adopt different states depending on their environment. Especially important are those that stop dividing and become invasive, leading to metastasis and resistance to drug and immunotherapies. One key gene encoding the AXL receptor has been linked to invasion and therapy resistance in many cancers, but how AXL might be activated as cell leave the primary tumor was unclear. This work revealed that invasive, but not proliferative melanoma cells, induce fatty acid release from adipocytes, and that oleic acid, a common fatty acid found in adipocytes and lymph, can activate AXL. The findings provide a major insight into phenotype-specific interactions with the microenvironment, and novel opportunities for therapeutic intervention.’
Read the full paper on the Genes & Development website: https://genesdev.cshlp.org/content/early/2025/02/27/gad.351985.124.full.pdf+html