Stromal lipid species dictate melanoma metastasis and tropism
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.
Authors
- Jean‐Christophe Marine (ORCID: https://orcid.org/0000-0003-2433-9837)
- Albert Koulman (ORCID: https://orcid.org/0000-0001-9998-051X)
- Timothy Budden (ORCID: https://orcid.org/0000-0003-2500-2814)
- Pedro Durao
- Karthik Mallela (ORCID: https://orcid.org/0000-0003-3330-955X)
- Caroline Gaudy‐Marqueste (ORCID: https://orcid.org/0000-0001-6955-5117)
- Alex von Kriegsheim (ORCID: https://orcid.org/0000-0002-4952-8573)
- Shilpa Gurung (ORCID: https://orcid.org/0000-0003-1577-5880)
- Esperanza Manrique
- Isabel Romero-Camarero (ORCID: https://orcid.org/0000-0002-2859-7641)
- Joanna Poźniak (ORCID: https://orcid.org/0000-0001-5739-1098)
- Fabio M. R. Amaral (ORCID: https://orcid.org/0000-0002-7917-5174)
- Victoria Sanz‐Moreno (ORCID: https://orcid.org/0000-0002-5096-9456)
- Alex R. Baker (ORCID: https://orcid.org/0000-0002-8365-8953)
- Eduardo Nagore (ORCID: https://orcid.org/0000-0003-3433-8707)
- Duncan L. Smith (ORCID: https://orcid.org/0000-0001-6791-450X)
- Amaya Virós (ORCID: https://orcid.org/0000-0001-5177-5015)
- Gilbert O. Fruhwirth (ORCID: https://orcid.org/0000-0002-1438-2674)
- Jair Marques (ORCID: https://orcid.org/0000-0002-8095-8475)
- Benjamin H. Jenkins (ORCID: https://orcid.org/0000-0002-3803-6418)
- David Millán-Esteban (ORCID: https://orcid.org/0000-0002-8066-1444)
- Tim C. P. Somervaille (ORCID: https://orcid.org/0000-0002-9188-4379)
- Sarah Craig (ORCID: https://orcid.org/0000-0003-1928-582X)
- Kang Zeng (ORCID: https://orcid.org/0000-0002-9989-474X)
- Luisa Motta
- Garry Ashton
- Laura Stennett
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- MRC Human Nutrition Research (GB)
- King's College London (GB)
- Aix-Marseille Université (FR)
- Breast Cancer Now (GB)
- Salford Royal NHS Foundation Trust (GB)
- Edinburgh Cancer Research (GB)
- Valencia Catholic University Saint Vincent Martyr (ES)
- University of Manchester (GB)
- London Cancer (GB)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Cancer Research UK Manchester Institute (GB)
- NIHR Manchester Biomedical Research Centre (GB)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1016/j.ccell.2025.04.001
- Citations
- 20
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 15.95
Funders
- Melanoma Research Alliance
- Harry J. Lloyd Charitable Trust
- Wellcome Trust
- UK Research and Innovation
- Barts Charity
- Cancer Research UK
- National Institute for Health and Care Research
- Kay Kendall Leukaemia Fund
- Rosetrees Trust
- LEO Pharma
- Manchester Biomedical Research Centre
- Spanish National Plan for Scientific and Technical Research and Innovation
- NIHR Cambridge Biomedical Research Centre