2. Academic Validation
  3. Stromal lipid species dictate melanoma metastasis and tropism

Stromal lipid species dictate melanoma metastasis and tropism

  • Cancer Cell. 2025 Jun 9;43(6):1108-1124.e11. doi: 10.1016/j.ccell.2025.04.001.
Shilpa Gurung 1,  Timothy Budden 1,  Karthik Mallela 1,  Benjamin Jenkins 2,  Alex von Kriegsheim 3,  Esperanza Manrique 4,  David Millán-Esteban 4,  Isabel Romero-Camarero 5,  Fabio Amaral 5,  Sarah Craig 1,  Pedro Durao 1,  Joanna Pozniak 6,  Laura Stennett 7,  Duncan Smith 8,  Garry Ashton 9,  Alex Baker 10,  Kang Zeng 10,  Gilbert Fruhwirth 7,  Victoria Sanz-Moreno 11,  Jair Marques 3,  Albert Koulman 2,  Jean-Christophe Marine 6,  Tim C P Somervaille 5,  Luisa Motta 12,  Caroline Gaudy-Marqueste 13,  Eduardo Nagore 4,  Amaya Virós 14
Affiliations

Affiliations

  • 1 Skin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, the University of Manchester, Manchester, UK.
  • 2 Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK; Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Fulbourn Road, Cambridge CB1 9NL, UK.
  • 3 CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 4 School of Medicine, Universidad Católica de Valencia, San Vicente Mártir, 46001 Valencia, Spain; Department of Dermatology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain.
  • 5 Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4GJ, UK.
  • 6 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
  • 7 Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Studies, King's College London, Guy's Campus, London, UK; School of Biomedical Engineering and Imaging Sciences, King's College London, St. Thomas' Hospital, London, UK.
  • 8 Proteomics, Cancer Research UK Manchester Institute, The University of Manchester, Manchester SK10 4TG, UK.
  • 9 Histology, Cancer Research UK Manchester Institute, The University of Manchester, Manchester SK10 4TG, UK.
  • 10 Visualisation, Irradiation & Analysis, Cancer Research UK Manchester Institute, The University of Manchester, Manchester SK10 4TG, UK.
  • 11 Cytoskeleton and Metastasis Team, The Breast Cancer Now Toby Robins Research Centre Division of Breast Cancer Research, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK; Centre for Tumour Microenvironment at Barts Cancer Institute, Queen Mary University of London, Charterhouse Square Campus, John Vane Science Centre, London, UK.
  • 12 Department of Histopathology, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK.
  • 13 Aix Marseille University, APHM, CRCM Inserm U1068, CNRS U7258, CHU Timone, Dermatology and Skin Cancer Department, Marseille, France.
  • 14 Skin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, the University of Manchester, Manchester, UK; NIHR Manchester Biomedical Research Centre, Manchester, UK; Department of Dermatology, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK. Electronic address: amaya.viros@cruk.manchester.ac.uk.
PMID: 40280124 DOI: 10.1016/j.ccell.2025.04.001
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.

Keywords

OXPHOS; aged skin; aging; lipid metabolism; liver tropism; melanoma; melanoma metastasis; metastasis; oxidative stress; tropism.

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