Targeting the Lipid Metabolism Proteins FASN and GPAM in Alveolar Type II Cells Decreases Lung Metastasis

Authors:
Open Access
Publisher website
Google Scholar
Abstract
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. Significance: Current therapies in oncology targeting the cancer or immune cell compartment of tumors show limited efficacy against breast cancer–derived metastases. We discovered that decreasing the lipid metabolism of lung resident AT2 cells is sufficient to impair lung metastasis growth in mice without apparent adverse effects.
Funding Information
  • European Molecular Biology Organization (ALTF 401-2022)
  • Fonds Wetenschappelijk Onderzoek (1231025N)
  • Gilead Research Scholars
  • Fonds Wetenschappelijk Onderzoek (12V9621N)
  • HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA-IF-2018-839896)
  • HORIZON EUROPE European Research Council (ERC-StG-101116912)
  • Deutsche Forschungsgemeinschaft (DFG 521676159)
  • National Health and Medical Research Council (GNT2025648)
  • National Health and Medical Research Council (GNT2025648)
  • HORIZON EUROPE European Research Council (ERC-CoG-101124557)
  • Fonds National de la Recherche Luxembourg (FNR-CORE C21/BM/15718879)
  • Chinese Government Scholarship
  • European Molecular Biology Organization (ALTF 13-2022)
  • Fonds Wetenschappelijk Onderzoek (1266225N)
  • Cancer Research UK (C57633/A25043)
  • Cancer Research UK (FC001223)
  • Cancer Research UK (C57633/A25043)
  • Cancer Research UK (C57633/A25043)
  • Wellcome Trust (FC001223)
  • Wellcome Trust (FC0010060)
  • Stichting Tegen Kanker (2022-173)
  • World Cancer Research Fund International (IIG_FULL_2023_001)
  • Fonds Wetenschappelijk Onderzoek
  • Fonds Baillet Latour
  • Fondation ARC pour la Recherche sur le Cancer
  • KU Leuven (METH/26/009)
  • KU Leuven (C14/21/114)
  • Belgian Cancer Foundation (C/2022/2046)
  • Fonds Wetenschappelijk Onderzoek (G082524N)
  • Breast Cancer Research Foundation (BCRF-24-212)

This publication has 75 references indexed in Scilit: