Stromal lipid species dictate melanoma metastasis and tropism.
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ICR Authors
Authors
Gurung, S
Budden, T
Mallela, K
Jenkins, B
von Kriegsheim, A
Manrique, E
Millán-Esteban, D
Romero-Camarero, I
Amaral, F
Craig, S
Durao, P
Pozniak, J
Stennett, L
Smith, D
Ashton, G
Baker, A
Zeng, K
Fruhwirth, G
Sanz-Moreno, V
Marques, J
Koulman, A
Marine, J-C
Somervaille, TCP
Motta, L
Gaudy-Marqueste, C
Nagore, E
Virós, A
Budden, T
Mallela, K
Jenkins, B
von Kriegsheim, A
Manrique, E
Millán-Esteban, D
Romero-Camarero, I
Amaral, F
Craig, S
Durao, P
Pozniak, J
Stennett, L
Smith, D
Ashton, G
Baker, A
Zeng, K
Fruhwirth, G
Sanz-Moreno, V
Marques, J
Koulman, A
Marine, J-C
Somervaille, TCP
Motta, L
Gaudy-Marqueste, C
Nagore, E
Virós, A
Document Type
Journal Article
Date
2025-06-09
Date Accepted
2025-04-01
Abstract
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.
Citation
Cancer Cell, 2025, 43 (6), pp. 1108 - 1124.e11
Source Title
Cancer Cell
Publisher
CELL PRESS
ISSN
1535-6108
eISSN
1878-3686