Targeting the Lipid Metabolism Proteins FASN and GPAM in Alveolar Type II Cells Decreases Lung Metastasis
Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell-derived lipids and whether AT2 cells can be targeted to reduce metastasis growth remains unknown. We discovered that breast cancer-derived lung metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients using spatial analysis. Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element-binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM). Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice. In summary, we discovered that overt metastases reprogram AT2 cells and that targeting the lipid metabolism of AT2 cells impairs metastasis growth.
Authors
- Mélanie Planque (ORCID: https://orcid.org/0000-0001-7052-7084)
- Kristien Borremans (ORCID: https://orcid.org/0000-0001-7047-1543)
- Jonas Dehairs (ORCID: https://orcid.org/0000-0002-6789-2264)
- Johannes V. Swinnen (ORCID: https://orcid.org/0000-0002-7720-5077)
- Janine Theile (ORCID: https://orcid.org/0009-0006-1155-7594)
- Josephine Bunch (ORCID: https://orcid.org/0000-0002-4257-1296)
- James S. McKenzie (ORCID: https://orcid.org/0000-0002-1007-317X)
- Josephine Van Cauwenberge (ORCID: https://orcid.org/0000-0001-9802-186X)
- Josep Tarragó‐Celada (ORCID: https://orcid.org/0000-0001-7322-9736)
- Xander Spotbeen (ORCID: https://orcid.org/0000-0002-1510-967X)
- Sebastian Igelmann (ORCID: https://orcid.org/0000-0001-6133-4184)
- Alina Dahlhaus (ORCID: https://orcid.org/0000-0001-9055-0695)
- Christine Desmedt (ORCID: https://orcid.org/0000-0002-5223-5579)
- Rory T. Steven (ORCID: https://orcid.org/0000-0002-6754-2424)
- Jiadong Mao (ORCID: https://orcid.org/0000-0002-3818-1981)
- Yulia Panina (ORCID: https://orcid.org/0000-0001-9165-455X)
- Jakub Idkowiak (ORCID: https://orcid.org/0000-0002-4336-9006)
- Vincen Wu
- Johannes Meiser (ORCID: https://orcid.org/0000-0002-9093-6210)
- Kim‐Anh Lê Cao (ORCID: https://orcid.org/0000-0003-3923-1116)
- Juan Fernández-García (ORCID: https://orcid.org/0000-0003-3422-3627)
- Paolo Inglese (ORCID: https://orcid.org/0000-0001-6179-9643)
- Zoltan Takats
- Hui-Chao Zhou
- Patricia Altea-Manzano
- Alex Dexter
- Weigang Cai
- Richard Mitter
- Sarah-Maria Fendt
- Xiao-Zheng Liu
- Ian S. Gilmore
- Avinash Ghanate
- Alejandro Suárez-Bonnet
- Mariia Yuneva
- Johannes Ceuppens
- Bin Yan
- Yiming Peng-Winkler
- Ilaria Malanchi
Institutions
- Royal Veterinary College (GB)
- National Physical Laboratory (GB)
- The University of Melbourne (AU)
- Breast Cancer Research Foundation (US)
- Rega Institute for Medical Research (BE)
- The Francis Crick Institute (GB)
- Düsseldorf University Hospital (DE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Luxembourg Institute of Health (LU)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Melbourne Genomics Health Alliance (AU)
- Heinrich Heine University Düsseldorf (DE)
- Imperial College London (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-03-04
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0191
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00