Title : Spatial multi-omics inference of diabetes-triggered pancreatic cancer growth: The key role of cholesterol-induced neutrophil extracellular
Abstract:
Objective: Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) are associated with poor clinical outcome, while the mechanism remains unclear. Metabolic reprogramming of cancer cells and immune compartments determines the anti-tumor immune response in PDAC. DM-derived metabolic reprogramming can alter the complex cross-talk between immune cells and associated immune factors that have profound effects on PDAC progression.
Methods: We propose an integrated spatially resolved multi-omics study to approach DM-associated cell-specific metabolic remodeling in the tumor microenvironment of PDAC. We establish a regulatory mechanism of DM influencing the interactions between tumor cells and immune cells which accelerates PDAC growth in human and mice.
Results: PDAC with DM displayed higher tumor-stage and lower tumor differentiation, which indicated poor clinical outcomes in patients. DM-associated spatially metabolic and transcriptional profiles suggested the importance of SREBP2-dependent cholesterol biosynthesis on aggravating PDAC progression. SREBP2-mediated cholesterol biosynthesis recruited neutrophils and accelerated neutrophil extracellular traps (NETs) formation through CXCL1-CXCR1/CXCR2 axis that promoted PDAC growth. Inhibition of SREBP2, pharmacological blockade of CXCL1 or NETs inhibition significantly restrained PDAC growth in DM mouse models.
Conclusion: Our study established a multi-omics network to discover the transcriptomic and metabolic mechanisms of diabetes promoting PDAC development, which provides an optimizing therapeutic strategy for PDAC with DM.
