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, which are mostly 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 metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients with breast cancer using spatial mass spectrometry imaging combined with immunohistochemistry and spatial transcriptomics. Mechanistically, we find that the secretome of the metastases contains IL-6 and formate, which increase the activity of the transcription factor sterol regulatory element-binding transcription factor 1 (SREBP-1). This in turn enhances 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 is sufficient to impair breast cancer-derived 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.