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. Overall design: 6–8-week-old female Balb/c mice were inoculated with 4T1 (1 x 10^6) cells in the mammary fat pad. Mice were euthanized after 21-23 days. Lungs from either tumour-bearing or control mice were taken for the analysis. Visium spatial transcriptomics analysis was carried out according to the manufacturer's instructions (10x Genomics) with the following parameters: Fresh-frozen mouse either control or metastatic lung tissues derived from 4T1 m.f.p. injection model was processed for spatial gene expression profiling using the 10x Genomics Visium Spatial Gene Expression platform (Visium Slide PN-2000233, SN: V13J17-305). Tissue sections were mounted on a Visium Spatial Gene Expression Slide with four capture areas, each containing ~5,000 spatially barcoded spots. Following fixation and hematoxylin and eosin (H&E) staining, tissue permeabilization was performed for 18 minutes—a duration determined through prior tissue optimization using the 10x Genomics Tissue Optimization protocol (CG000238). mRNA released from permeabilized tissue was hybridized to oligonucleotides on the slide, and reverse transcription was carried out in situ to generate spatially barcoded cDNA. Subsequent library preparation followed the manufacturer's protocol (Visium Spatial Gene Expression Reagent Kits User Guide, CG000239 Rev F), including second-strand synthesis, cDNA amplification, enzymatic fragmentation, end repair, adaptor ligation, and sample index PCR. Libraries were sequenced on an Illumina platform (NovaSeq 6000) using paired-end sequencing (Read 1: 28 bp, Read 2: 90 bp) at a target depth of (50k reads per cell/spot).