Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion
Squamous cell carcinomas (SCCs) originate in epithelial tissues of older individuals who have been exposed to environmental carcinogens. Despite overlapping clinical hallmarks, SCCs from different anatomic sites have different prognoses. Here we show that fibroblasts confer site-specific cues that determine SCC proliferation and invasion. Oral and lung fibroblasts have distinct lipid metabolism, transferring unique lipids to SCC cells that promote epithelial-to-mesenchymal transition, and oral and lung SCC invasion. Whereas oral fibroblasts transfer sphingomyelins, which activate the ceramide-sphingosine-1-phosphate-STAT3 pathway and promote oral SCC invasion, lung fibroblasts transfer triglycerides to lung SCCs, thereby triggering cholesterol synthesis and invasion, which is associated with poor survival. By contrast, dermal fibroblasts are lipid poor, and cutaneous SCC is less invasive. Our data indicate that targeting fibroblast lipid synthesis and SCC lipid uptake or breakdown inhibits oral and lung epithelial cancer invasion.
Authors
- C. Harwood
- Timothy Budden (ORCID: https://orcid.org/0000-0003-2500-2814)
- Carlos López‐García (ORCID: https://orcid.org/0000-0001-9848-8216)
- Antonio Rullan (ORCID: https://orcid.org/0000-0002-7365-9629)
- Ben O’Leary (ORCID: https://orcid.org/0000-0002-1092-9169)
- Lijie An (ORCID: https://orcid.org/0009-0007-1581-7979)
- Charlotte Russell (ORCID: https://orcid.org/0000-0002-8194-8033)
- Alex von Kriegsheim (ORCID: https://orcid.org/0000-0002-4952-8573)
- Shilpa Gurung (ORCID: https://orcid.org/0000-0003-1577-5880)
- Malin Pedersen (ORCID: https://orcid.org/0000-0003-1887-733X)
- Amaya Virós (ORCID: https://orcid.org/0000-0001-5177-5015)
- Luisa Motta
- Martha Gutteridge
- Claus Jorgensen
- Caroline Gaudy-Marqueste
- Noah Palombo
- Jair Marques
- Kevin Harrington
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- University of Liverpool (GB)
- Bangor University (GB)
- Queen Mary University of London (GB)
- Aix-Marseille Université (FR)
- Edinburgh Cancer Research (GB)
- National Institute for Health and Care Research (GB)
- Evolutionary Genomics (United States) (US)
- Salford Royal Hospital (GB)
- Cancer Research UK Manchester Institute (GB)
- Genomics England (GB)
- NIHR Manchester Biomedical Research Centre (GB)
- Hôpital de la Timone (FR)
- University College London (GB)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-04-27
- DOI
- https://doi.org/10.1038/s42255-026-01514-y
- Citations
- 1
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 12.65
Funders
- Melanoma Research Alliance
- Royal Marsden NHS Foundation Trust
- Cancer Research UK