An intron retention-derived secreted Endoglin Isoform as a circulating biomarker in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective strategies for early detection or prognostic assessment. Endoglin (CD105) is an endothelial receptor best known for its roles in vascular development and tumor angiogenesis, and its only recognized circulating form arises through proteolytic shedding of the full-length receptor. Here, we report a pancreatic tumor-derived secreted endoglin isoform that is molecularly distinct from all known endoglin variants, enabling the development of an isoform-specific antibody for selective detection. Through integrated transcriptomic, biochemical, and translational analyses, we identified a truncated endoglin isoform generated by intron retention that contains a unique C-terminal peptide absent from canonical endoglin. This isoform was detected in human PDAC cell lines, orthotopic xenografts, primary patient tumors, patient sera, and the KPC genetically engineered mouse model, demonstrating conservation across clinically relevant systems. Tissue microarray analysis revealed that the isoform is prevalent in PDAC and represents a major subset of endoglin-positive tumors, while immunoprecipitation and a newly developed sandwich ELISA confirmed its presence in patient circulation, supporting its potential as a blood-based biomarker. Together, these findings identify a previously unrecognized, tumor-derived secreted endoglin isoform and highlight intron retention as source of circulating protein biomarkers in pancreatic cancer.