PROJECT SUMMARY – Core 3: Mouse Models Core The Mouse Models Core (MM Core) will provide essential, value-added services in support of all P01 projects. As all projects propose preclinical experimental therapeutic trials with murine models, such trials will benefit from expert professional staff where uniform procedures and standardized imaging protocols would enable comparison of therapeutic regimens across the P01 and ensure reliability, reproducibility, and consistency of all proposed studies. In support of these goals, the MM Core has three Specific Aims. The First Aim of the MM Core is to provide orthotopic transplantation services of mouse and human material, which will be used to identify cell compartment-specific vulnerabilities. The MM Core will transplant mouse and human pancreatic cancer organoids to enable analyses of intrinsic and acquired resistance, and to test new strategies for overcoming these challenges that have historically limited long-term therapeutic successes. The MM Core will use orthotopic transplantation to: 1) determine the ability of HDAC inhibition to synergize with DNA damaging agents, reprogram fibroblast heterogeneity, and potentiate the response to immunotherapy (Project 1), 2) assess the impact of LIF and STAT3 loss in the tumor microenvironment on tumor growth (Project 2), and 3) determine the extent to which CA-19-9 levels affect autophagy (Project 3). The Second Aim of the MM Core is to provide access to enough tumors generated in the KPC autochthonous model to perform survival studies on the most promising drug combination regimens identified in each Research Project. The KPC model is challenging, as the mice must be bred and genotyped, and then animals with tumors must be enrolled at appropriate and reproducible time points using ultrasound imaging to assess tumor size. The MM Core will enable the KPC model to be used in a way that benefits from a dedicated staff with expertise in the specialized diagnostic techniques required to enroll animals harboring tumors between 5-8 mm. This will ensure consistency in the husbandry needed for survival studies. To minimize the number of animals required, and costs incurred, decisions on which drug combinations will be used for KPC survival studies will be based on evaluation of all orthotopic transplantation data by the Project Leads in consultation with the EAB. Drug combinations showing significant survival benefit in the KPC model will then be evaluated in a second trial to ensure reproducibility. The Third Aim is designed to provide access to intraductal injection of viral Cre to create pancreas-specific deletions in mice encoding complex allele combinations. This unique and demanding technique will be optimized by the Core to achieve uniformity and reproducibility. Among other applications, this procedure will be used extensively in Project 3 to delineate the role of AMPK and ULK1/2 in tumorigenesis. Taken together, the MM Core will provide reliable, reproducibl...