Spatially resolved subtype progression reveals metabolic vulnerabilities in pancreatic ductal adenocarcinoma.

The basal and classical subtypes - driven by glycolysis versus lipid metabolism - have distinct prognostic implications. We mapped PDAC molecular subtype heterogeneity, capturing spatially-resolved gene expression signatures and generating a comprehensive high-resolution dataset of 42,035 spatial spots.

Subtype assignments were validated via multiplex immunofluorescence and quantitative analyses in patient-derived organoids. Our analysis resolved cancer cell signatures, deconvoluted intra-tumoral heterogeneity, and delineated a classical-to-basal trajectory. We identified metabolically ‘hot’, high-grade tumor niches characterized by concurrent enrichment of glycolysis and lipogenesis across both subtypes, nominating them as subtype-agnostic therapeutic targets.