Metabolic Dynamics in Pancreatic Cancer

Pancreatic cancer exhibits profound metabolic plasticity as malignant cells adapt to a hypovascular, nutrient-poor stroma. Oncogenic mutations, notably KRAS, reprogramme central carbon metabolism to fuel biomass production, maintain redox homeostasis and support rapid proliferation. Tumour cells co-opt diverse nutrient sources—including glucose, glutamine, lipids and extracellular macromolecules—by engaging pathways such as aerobic glycolysis, non-canonical glutamine catabolism, autophagy and micropinocytosis. Reciprocal interactions with cancer-associated fibroblasts, immune cells and the extracellular matrix further shape metabolic landscapes via paracrine nutrient exchange, epigenetic remodelling and signalling crosstalk. This adaptive flexibility underpins aggressive growth, chemoresistance and metastatic spread but also reveals therapeutic vulnerabilities. By elucidating key enzymes, transporters and stromal contributions, researchers are identifying targets for combinatorial strategies that may augment conventional chemotherapy. International efforts to translate these insights into metabolism-directed therapies and predictive biomarkers hold promise for improving outcomes in a disease with one of the lowest survival rates.

Research from Nature Portfolio

Recent studies have identified alternative nutrient axes that sustain pancreatic tumours under stress. One investigation revealed that uridine-derived ribose fuels central carbon metabolism and redox balance via uridine phosphorylase 1, enabling survival in glucose-deprived conditions. A separate report demonstrated that induced hyperglycaemia suppresses glutathione biosynthesis through downregulation of glutamate-cysteine ligase catalytic subunit, thereby enhancing the oxidative efficacy of standard chemotherapy. More recently, research has uncovered that stromal fibroblast-derived acetate is channelled by acetyl-CoA synthetase 2 to modulate histone acetylation and polyamine homeostasis through an ACSS2–SP1–SAT1 axis, promoting tumour cell survival in an acidic microenvironment; pharmacological or genetic disruption of this pathway reduces tumour burden in vivo.

Metabolic Dynamics in Pancreatic Cancer publication trend

The graph below shows the total number of articles in metabolic dynamics in pancreatic cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Warburg effect: Elevated glycolysis despite the presence of oxygen, supplying energy and biosynthetic precursors to proliferating tumour cells.

Tumour microenvironment: The complex milieu of cancer cells, stromal fibroblasts, immune cells, extracellular matrix and signalling molecules surrounding a tumour.

Redox homeostasis: The balance between production and elimination of reactive oxygen species to prevent oxidative damage and support cellular survival.

Autophagy: A regulated intracellular process that degrades and recycles cytoplasmic components, providing nutrients under conditions of stress.

Micropinocytosis: A form of endocytosis in which cells engulf extracellular fluid and macromolecules via plasma membrane invaginations to obtain nutrients.

References

1. Uridine-derived ribose fuels glucose-restricted pancreatic cancer. Nature (2023).
2. Increased glucose availability sensitizes pancreatic cancer to chemotherapy. Nature Communications (2023).
3. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2–SP1–SAT1 axis. Nature Cell Biology (2024).
4. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Molecular Cancer (2020).
5. Metabolism addiction in pancreatic cancer. Cell Death & Disease (2014).