| First Author | Ma Z | Year | 2026 |
| Journal | Gastroenterology | Volume | 170 |
| Issue | 4 | Pages | 735-752 |
| PubMed ID | 41553309 | Mgi Jnum | J:378495 |
| Mgi Id | MGI:8281477 | Doi | 10.1053/j.gastro.2025.09.032 |
| Citation | Ma Z, et al. (2026) ENPP1-Regulated Extracellular Purine Metabolism Drives Pancreatitis-Mediated Pancreatic Cancer. Gastroenterology |
| abstractText | BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The study results identified ENPP1 as a contributor to pancreatitis-mediated pancreatic cancer and a potential therapeutic target for pancreatic carcinogenesis. |
