ENPP1-Regulated Extracellular Purine Metabolism Drives Pancreatitis-Mediated Pancreatic Cancer.

Abstract

Patients with chronic pancreatitis (CP) have a higher risk of developing pancreatic ductal adenocarcinoma (PDAC). Although pancreatitis has been found to promote PDAC initiation and progression, its role in PDAC tumorigenesis remains poorly understood. A multiomics analysis of the transcriptome, proteome, and metabolome was performed in human pancreatic samples from patients with CP and CP-related PDAC (CP-PDAC). The CP-PDAC model was constructed in Ptf1a^Cre/+; LSL-Kras^G12D/+ mice and Ptf1a^Cre/+; LSL-Kras^G12D/+; ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) mice. Single-cell sequencing analysis of pancreatic tissue samples from Ptf1a^Cre/+; LSL-Kras^G12D/+ mice and Ptf1a^Cre/+; LSL-Kras^G12D/+; Enpp1 mice revealed the role of the immune microenvironment in the progression from pancreatitis to cancer. Pharmacologic ENPP1 inhibition was studied in the orthotopic transplantation model and CP-PDAC model mice. Multiomics analysis of samples from patients with CP and CP-PDAC revealed that ENPP1-regulated extracellular purine metabolism plays an important role in pancreatitis-cancer transformation. Mechanistically, inflammatory damage to pancreatic acinar cells leads to the release of purine nucleotide metabolites, which are degraded by ENPP1-CD73 on the surface of pancreatic stellate cells into adenosine. This process activates pancreatic stellate cells and promotes fibrosis. Activated pancreatic stellate cells then release CXCL17, which recruits myeloid-derived suppressor cells and regulatory T cells in the microenvironment, resulting in immunosuppressive effects. Finally, ENPP1 was confirmed to be an effective target for immunotherapy in PDAC and early intervention in pancreatitis-cancer transformation. The study results identified ENPP1 as a contributor to pancreatitis-mediated pancreatic cancer and a potential therapeutic target for pancreatic carcinogenesis.