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Global Protease Activity Profiling Provides Differential Diagnosis of Cystic Precursor Lesions of Pancreatic Cancer

Pancreatic cysts are being detected at an increasing rate and are estimated to be present in 2 percent of the adult population. Unfortunately, current preoperative diagnostics do not sufficiently distinguish benign cystic lesions from those that harbor malignant potential. Missregulated pericellular proteolysis is a hallmark of invasive cancer, and therefore, we used a global substrate profiling strategy to discover differentiating protease activities in patient cyst fluid obtained through minimally invasive endoscopic sampling. We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in mucinous cysts. Profiling of gastricsin and cathepsin E activity using fluorescent peptide substrates differentiated mucinous from nonmucinous cysts with high sensitivity and specificity in a 110 patient cohort. Of particular note, gastricsin activity analysis demonstrated a specificity of 100% and sensitivity of 93%, significantly outperforming the most widely used biomarker, carcinoembryonic antigen. We propose that activity‐based detection of gastricsin and cathepsin E has the potential to replace current diagnostic tests for differentiating mucinous from nonmucinous cysts, leading to improved clinical management of these challenging and highly prevalent lesions.