Abstract Core 2 Core 2, Cell and Whole Animal Genetic Engineering, will provide both projects with genetically engineered cell lines and mice for analyzing cell and/or tumor behavior under a variety of conditions. The core brings together expertise from two highly trained mouse and somatic cell geneticists, Dr. David Largaespada and Dr. Anindya Bagchi, both with expertise in modeling cancer in mice and with a wide array of cells. Thus, this core will generate two specific resources for both projects #1 and #2. The first is cohorts of mice that reliably develop pancreatic, glioma or medulloblastoma tumors due to the inheritance of germline transgenes, mutant alleles in their endogenous locus, or due to transposon-mediated gene delivery to the brain. Likewise, Core 2 will support studies perturbing the genetic events examined in each project. Additional models will be developed as needed. The models will be provided to project #1 and #2 scientists in age-matched cohorts and of both genders. These models are based both on the published literature well known to Dr. Largaespada, Dr. Bagchi and Dr. Provenzano, as well as technologies developed in the Largaespada lab. Specifically, these will be models of glioma and medulloblastoma initiated in mice by transposon delivery of shRNA and cDNAs. A second resource is to provide genetically altered human cancer cell lines for project #1 and #2. These cell lines will harbor loss of function mutations, or specific single nucleotide variants (SNV), in genes of interest. They will be produced using TAL endonuclease or CRISPR/Cas9 gene targeting, without or with oligonucleotide substrates, to create “knockout” cell lines due to imprecise non-homologous end joining (NHEJ) in the former case, or SNVs via homology directed repair (HDR) in the latter case.