Core B (Modeling & Experimental Therapeutics Core) - Abstract/Summary Genetically engineered mouse (GEM) models remain central to virtually all aspects of this P01 and have contributed significantly to our understanding of both mouse and human pancreatic cancer. GEM models, particularly those with inducible oncogenes, have enabled (i) elucidation of the role of specific genetic/pathway alterations in tumor biological mechanisms such as autophagy and immunity, (i) dissection of cooperative interactions between genetic elements such Kras* and different tumor suppressors such as p16ink4a, p53 and Smad4, and (iii) deconvolution of the heterotypic interactions across different cell types of the tumor microenvironment such as Kras* in cancer cells and TGFb in immune cells. In this renewal, two reasons prompted us to establish this new Core. First, the extreme allelic complexity of the models employed in each Project will benefit from dedicated sophisticated engineering. Along these lines, it is worth noting that our models may harbor as many as ten genetic alterations. Core B’s ES-GEM system serves as a powerful platform to introduce new alleles into existing multi-allelic ES lines harboring core PDAC-relevant alleles. Second, nearly all aims propose preclinical experimental therapeutic trials with GEM models. Such trials will benefit from expert execution with professional staff where standardized protocols would enable comparison of therapeutic regimens across the P01. Here again, the ES-GEM system helps tremendously as it enables highly efficient generation of large cohorts from one or two rounds of blastocyst injection to produce PDAC-prone mice that can be enlisted into multi-arm trials. The ES-GEM system has been proven to generate experimental cohorts with all the characteristics of a germline model. In addition, this approach dramatically reduces time and cost associated with large breeding colonies for therapeutic experiments.