Journal article
Fatty acid uptake activates an AXL-CAV1-β-catenin axis to drive melanoma progression
- 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.
- Publication status:
- Published
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 22.5MB, Terms of use)
-
(Preview, Supplementary materials, pdf, 9.9MB, Terms of use)
-
- Publisher copy:
- 10.1101/gad.351985.124
Authors
+ Marie Curie
More from this funder
- Funder identifier:
- https://ror.org/02aqv1x10
- Grant:
- FP7-PEOPLE: PIEF-GA2013-626098
+ European Molecular Biology Organization
More from this funder
- Funder identifier:
- https://ror.org/04wfr2810
- Grant:
- ALTF 800–2013
+ Fundação para a Ciência e Tecnologia
More from this funder
- Funder identifier:
- https://ror.org/00snfqn58
- Grant:
- 2021.05801.BD
- PTDC/ MED-ONC/5553/2020
+ Agencia Estatal de Investigación
More from this funder
- Funder identifier:
- https://ror.org/003x0zc53
- Grant:
- MCIN/AEI/10.13039/501100011033
- PID2021-127645OA-I00
- PID2023-151128OB-I00
- PID2019-104867RB-I00
- Publisher:
- Cold Spring Harbor Laboratory Press
- Journal:
- Genes & Development More from this journal
- Volume:
- 39
- Issue:
- 7-8
- Pages:
- 463-489
- Place of publication:
- United States
- Publication date:
- 2025-02-27
- Acceptance date:
- 2025-01-27
- DOI:
- EISSN:
-
1549-5477
- ISSN:
-
0890-9369
- Pmid:
-
40015991
- Language:
-
English
- Keywords:
- Pubs id:
-
2094049
- Local pid:
-
pubs:2094049
- Deposit date:
-
2025-05-01
- ARK identifier:
Terms of use
- Copyright holder:
- Chocarro-Calvo et al.
- Copyright date:
- 2025
- Rights statement:
- © 2025 Chocarro-Calvo et al. This article, published in Genes & Development, is available under a Creative Commons License (Attribution-Non Commercial 4.0 International), as described at http://creativecommons. org/licenses/by-nc/4.0/.
If you are the owner of this record, you can report an update to it here: Report update to this record