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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Cancer cell
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40280124/ |
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Table of Contents:
- Stromal lipid species dictate melanoma metastasis and tropism. Gurung, Shilpa Budden, Timothy Mallela, Karthik Jenkins, Benjamin von Kriegsheim, Alex Manrique, Esperanza Millán-Esteban, David Romero-Camarero, Isabel Amaral, Fabio Craig, Sarah Durao, Pedro Pozniak, Joanna Stennett, Laura Smith, Duncan Ashton, Garry Baker, Alex Zeng, Kang Fruhwirth, Gilbert Sanz-Moreno, Victoria Marques, Jair Koulman, Albert Marine, Jean-Christophe Somervaille, Tim C P Motta, Luisa Gaudy-Marqueste, Caroline Nagore, Eduardo Virós, Amaya Animals Tumor Microenvironment Melanoma Humans Mice Oxidative Phosphorylation Signal Transduction Cell Line, Tumor Lipid Metabolism Oxidative Stress Neoplasm Metastasis Lung Neoplasms Liver Neoplasms Stromal Cells Mice, Inbred C57BL Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.