Targeting the lipid metabolism proteins FASN and GPAM in alveolar type II cells decreases lung metastasis
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Xiao-Zheng Liu Yulia Panina Weigang Cai Juan Fernández-García Yiming Peng-Winkler Jiadong Mao Alina Dahlhaus Hui-Chao Zhou Ming Liu Melanie Planque Johannes Ceuppens Sebastian Igelmann Xander Spotbeen Jakub Idkowiak Jonas Dehairs Janine Theile Konstantinos Axarlis Kristien Borremans Josephine Van Cauwenberge Avinash Ghanate Josep Tarrago Celada Alejandro Suárez-Bonnet Richard Mitter Vincen Wu Paolo Inglese James S McKenzie Rory T Steven Alex Dexter Bin Yan Jean-Luc Vorng Zoltán Takáts Josephine Bunch Ian S Gilmore Peter Carmeliet Christine Desmedt Ilaria Malanchi Johannes V Swinnen Patricia Altea-Manzano Kim-Anh Lê Cao Johannes Meiser Mariia Yuneva Sarah-Maria Fendt
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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.
Journal details
Journal
Cancer Discovery
Volume
16
Issue number
7
Pages
1412-1435
Available online
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Publisher website (DOI)
10.1158/2159-8290.CD-25-0191
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Europe PubMed Central
41778850
Pubmed
41778850
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