Arid1a loss accelerates pancreatic ductal adenocarcinoma precursor formation

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PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) patients have an expected 5-year survival of less than 10% in large part to the lack of effective therapeutics. Detailed understanding of the molecular mechanisms that drive pancreas cancer formation and progression are desperately needed to develop new therapies for this intractable disease. ARID1A, which is part of the SWI/SNF chromatin remodeling complex, is one of the most commonly mutated genes in PDAC but the effects of the mutation are unknown. We found that Arid1a deletion in mouse leads to accelerated formation of pancreatic intraepithelial neoplasms (PanIN), which are precursors to PDAC. We also found that protein synthesis is aberrantly elevated after Arid1a loss, which suggests that protein translation may be a therapeutic target. The overall objective of this study is to determine how ARID1A deletion in acinar cells accelerates the formation PanIN by determining 1) if Arid1a mutations accelerate not only the formation of PanIN but also their progression to PDAC, 2) the epigenetic effects of Arid1a deletion in the pancreas, and 3) if blocking protein synthesis can prevent Arid1a induced PanIN formation. At the completion of our proposal, we expect that we will better understand how ARID1A and chromatin remodeling affect pancreas cancer initiation and progression and potentially identify new therapeutic targets. The proposed project will be part of my continued training and development to become an independent investigator. The training plan includes coursework, hands-on experience, and closed mentorship from a team of experienced and accomplished scientists. Dr. Hao Zhu will be my co-mentor. He is an expert in the role of SWI/SNF in liver regeneration and cancer. Dr. Rolf Brekken, an expert in tumor microenvironment and angiogenesis and has extensive experience studying pancreas cancer in mice, will be my co-mentor. My scientific advisory team includes 1) Dr. Sean Morrison, a Howard Hughes Investigator and an expert in hematopoietic stem cell biology, including protein synthesis, 2) Dr. Jian Xu, an expert in epigenetics and protein synthesis 3) Dr. Joshua Mendell, a Howard Hughes Investigator and an expert in post-transcription gene regulation. They will provide guidance for my science, mentorship for career development, and technical support. The Department of Surgery has committed to protecting 80% of my time for research endeavors, fully supporting my salary, and maintaining these arrangements regardless of the outcome of this award application. The Zhu lab is based in the Children’s Research Institute, which is headed by Dr. Morrison. It is a multidisciplinary institute that focuses on stem cell biology, cancer, and metabolism. It is an incredibly collaborative and well- resourced environment and is an outstanding training environment.