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Spatially resolved subtype progression reveals metabolic vulnerabilities in pancreatic ductal adenocarcinoma

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) exhibits profound molecular heterogeneity and poor prognosis, necessitating novel tailored therapies. 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. Preclinical models demonstrated that despite the basal subtype’s glycolysis dependence, both classical and basal tumors are susceptible to glycolysis inhibition. This work challenges the dogma of subtype-specific therapeutic silos and demonstrates highly adaptable energetic niches as reservoirs to drive tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309669 | GEO | 2026/04/22

REPOSITORIES: GEO

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

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