Absence of Activating Transcription Factor 3 Reduces Severity of Recurrent Pancreatitis and K-RAS Mediated PDAC in Mice

Nawab Azizi, The University of Western Ontario

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a terminal cancer projected to become the leading cause of cancer-related deaths in North American by the year 2030. Constitutive activation of KRAS is seen in >90% of PDAC cases. In addition to oncogenic KRAS activity, pancreatic injury is key contributor to PDAC initiation and progression. Activating transcription factor 3 (ATF3) is required for the formation of pre-neoplastic lesions in acute pancreatitis. However, unlike recurrent or chronic forms of pancreatitis, acute pancreatitis is not predictive of PDAC. Therefore, the goal of this thesis is to determine the role of ATF3 in recurrent pancreatitis and PDAC. I hypothesize that ATF3 is required for persistent acinar-to-ductal cell metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) in recurrent pancreatitis and PDAC. To address this hypothesis, I used mice carrying a targeted deletion of the Atf3 translation start site (Atf3^-/-) and exposed them to an experimental model of recurrent pancreatic injury or bred them with mice allowing inducible activation of oncogenic KRAS (KRAS^LSL-G12D/+) specifically in pancreatic acinar cells. The absence of ATF3 reduced ADM and improved pancreatic tissue regeneration in response to recurrent pancreatitis. In addition, KRAS-G12D mice lacking Atf3 showed reduced high grade PanIN lesions compared to mice expressing KRAS-G12D and ATF3. These results suggest an important role for ATF3 in PDAC initiation and progression from recurrent forms of pancreatitis.