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Glycolytic heterogeneity drives metabolic-targeted therapy in PDAC

ABSTRACT: Background: Pancreatic ductal adenocarcinoma is classically characterized as a glycolytic tumor. However, the extent and implications of metabolic heterogeneity within PDAC remain poorly defined. This study aimed to determine whether glycolytic activity follows a consistent expression pattern across PDAC patients and to explore how metabolic diversity influences therapeutic vulnerability. Methods: We employed spatial transcriptomics in six, ex vivo, primary human PDAC specimens, complemented by single-cell and bulk RNA sequencing, to map glycolytic heterogeneity in PDAC. Patient-derived cell models, representative of distinct glycolytic phenotypes, were used to assess metabolic and antiproliferative responses to glycolytic pathway inhibition. A comprehensive multi-omics strategy—including metabolomics, proteomics, and lipidomics—was integrated through a robust bioinformatics pipeline to dissect pathway-specific variations and integromics. Results: PDAC tumors displayed marked glycolytic heterogeneity, with distinct transcriptional profiles that preserved cell identity and spatial organization. These glycolytic patterns correlated with clinical outcomes, highlighting their potential prognostic value. Functional studies strengthen differential sensitivity to metabolic inhibitors in models with opposite glycolytic activity, demonstrating both the therapeutic relevance of PDAC glycolytic stratification and highlighting the potential of metabolic targeting. Conclusions: Our findings uncover a clinically relevant metabolic heterogeneity in PDAC, offering a novel stratification framework based on glycolytic profiling. This approach may allow the selection of patients for tailored metabolic therapies, advancing precision oncology in pancreatic cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303338 | GEO | 2025/11/28

REPOSITORIES: GEO

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Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC. Primary pancreatic tumor lines were established from p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice. Five independent tumor lines (iKras1-5) were used for pancreatic injection into nude mice to generate orthotopic tumors. The mice were kept on doxycycline for 2 weeks until obvious tumor formation. Half of the animals were pulled off doxycycline for 24 hours. Tumors with over 75% cellularity were collected for total RNA prepartion. For in vitro expression profiles, the same five tumor lines were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two independent tumor lines from LSL-KrasG12D p53L+ tumors were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared.

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Glycolytic heterogeneity drives metabolic-targeted therapy in PDAC

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