Master of Science
Physiology and Pharmacology
Pin, Christopher L.
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 (KRASLSL-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.
Summary for Lay Audience
This body of work examines the role of a protein called Activating Transcription Factor 3 (ATF3) in experimental models of pancreatitis and pancreatic cancer in mice. Pancreatitis is the inflammation of the pancreas as a result of injury, which increases the susceptibility of pancreatic cancer development. Previous work done in out laboratory looked at acute forms of pancreatitis and showed that the germ-line loss (laboratory techniques involving specific deletion of a gene in embryonic stem cells) of Atf3 expression was beneficial for pancreatic tissue regeneration. Next, I wanted to know if the loss of ATF3 was also beneficial in the context recurrent forms of pancreatitis (greater susceptibility for pancreatic cancer in comparison to acute forms) and pancreatic cancer. My work showed that mice lacking ATF3 expression in recurrent forms of pancreatitis had better tissue regeneration and lower number of lesions that have the potential of developing into cancer. In my pancreatic cancer model, the loss of ATF3 reduced the number of highly developed lesions. My results indicate that there may be a potential in therapeutically targeting ATF3 in pancreatic cancer for better outcome.
Azizi, Nawab, "Absence of Activating Transcription Factor 3 Reduces Severity of Recurrent Pancreatitis and K-RAS Mediated PDAC in Mice" (2019). Electronic Thesis and Dissertation Repository. 6259.
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Available for download on Friday, October 01, 2021