Cancer cell · 2025
Stromal lipid species dictate melanoma metastasis and tropism.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.