Aberrant lipid metabolic reprogramming accelerates gastric cancer malignancy through diminished ceramide-driven ALPP inhibition

Metabolic reprogramming is a canonical hallmark of cancer that reflects the biological properties of tumors. Deciphering the metabolic profiles and key metabolites involved in tumor progression is pivotal for advancing metabolism-centric precision oncology against gastric cancer (GC). In this study, we integrated widely targeted metabolomics, spatial metabolomics, quantitative lipidomics, whole-exome sequencing, single-cell, and spatial transcriptomics techniques to elucidate lipid metabolic reprogramming in tumor samples and mouse models of GC. In vitro experiments were conducted to explore the biological functions and mechanisms of action of ceramide in tumor cells. Widely targeted metabolomics revealed dysregulated lipid metabolism and arginine biosynthesis in the orthotopic mouse model. Spatial metabolomics indicated critical roles for glycerophospholipids and glycerolipids in the tertiary lymphoid structures. Moreover, the lipid metabolic changes were explored at the genomic and transcriptional levels. Based on quantitative lipidomics, dysregulated sphingolipid metabolism was identified in GC progression with downregulation of ceramides. Further experiments suggested that ceramides have tumor-suppressive functions and pro-tumor alkaline phosphatase, placental (ALPP) were suppressed by ceramides in GC. Our study integrated multi-omics approaches to profile metabolic reprogramming from multiple perspectives, with a particular focus on lipid metabolism in GC. In addition, we proposed that ceramides exert anti-cancer effect by suppressing ALPP, providing potential target for metabolism-targeted therapeutic intervention in GC.