Single-cell Sequencing Analysis Reveals Cell Subtypes With High Expression of Coagulation Factor 3 and Their Possible Roles in Pancreatic Ductal Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a high incidence of thrombosis. Coagulation factor 3 (F3) plays a key role in initiating the coagulation pathway. This study identified cell subpopulations that highly express F3 and explored their potential roles in PDAC. Methods: This study evaluated 1837 patients with PDAC from two cancer hospitals between November 1, 2023, and November 30, 2024. The analyses included assessing coagulation and fibrinolysis indicators, and employing single-cell sequencing technology to examine the tumor microenvironment in freshly resected PDAC tissues. Findings were validated using the Gene Expression Omnibus database. Results: Over half of the patients (54.98%) with PDAC showed abnormal coagulation indicators. F3 mRNA and protein levels were higher in PDAC tissues than in normal tissues. This high F3 expression in PDAC was associated with a poor prognosis (p < 0.01). Analysis of 33,300 cells from freshly resected PDAC tissues showed high F3 expression in cancer-associated fibroblasts (CAFs) and ductal cells. Subsequent subtype analysis indicated that ductal cell 1 (tumor cells) and inflammatory CAFs (iCAFs) exhibited high F3 expression. Pseudotime trajectory analysis showed that iCAFs were prevalent in the earlier part of the pseudotime pathway. Notably, pathways associated with inflammation, phosphoinositide 3-kinase/Akt signaling, and coagulation and complement were significantly enriched in iCAFs. In addition, the interaction between iCAFs and tumor cells was regulated by growth factor receptor–ligand pairings. “GSE212966” and “GSE197177” data confirmed these results. Conclusion: The high expression of F3 in specific iCAF subtypes suggests a role in PDAC hypercoagulability and tumor progression. Targeting these iCAF subtypes could provide potential strategies for treating PDAC.