PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Understanding the mechanisms that lead to the development of pancreatic cancer and to identify markers that distinguish between non-cancerous and cancerous lesions is the greatest hope for early detection and early treatment of patients. This proposal focusses on identifying early detection markers that would allow resection of tumors at a time point where they are still local. It is our hypothesis that pancreatic high-grade lesions significantly distinguish from low- grade lesions by expressing PADI1. We further hypothesize that PADI1 and its citrullinated substrates can be detected in pancreatic biopsy and may form a panel of markers specific for early detection of PDA. To test this we will: verify PADI1 as a specific marker for HG lesions and test its presence in liquid biopsies (Specific Aim 1); characterize citrullinated fibrinogen as a PADI1 substrate and marker for pancreatic cancer (Specific Aim 2); and identify pancreas cancer specific PADI1-citrullinated substrates (intracellular and secreted) in lesions and in liquid biopsy (Specific Aim 3). Successful completion of our project will identify secreted protein markers that are detectable in easily accessible liquid biopsy (blood serum) and distinguish between pancreatic non-cancerous lesions and PanIN3 (carcinoma in situ) and PDA lesions.