Core A: Modeling Core

PROJECT SUMMARY/ABSTRACT – MODELING CORE The Modeling Core forms a foundation for the P01 application by providing critical resources including unique types of specimens and services to all three projects, to support the overarching goals of identifying the molecular drivers of prostate cancer (PC) and biomarker development. The performance of translational research mandates that investigators have ready access to well-characterized and relevant biological models. To accomplish the objectives of the Core, to support the P01 Projects, we designed three Specific Aims: Specific Aim 1. Maintain and distribute patient-derived xenograft (PDX) models and cell lines, and run preclinical studies. The Modeling Core will provide a unique set of metastatic castrate resistant prostate cancer (mCRPC) LuCaP patient derived xenograft (PDX) models that represent the heterogeneity observed in patients. The Modeling Core will also perform pre-clinical studies using these resources where appropriate for the Project goals. Specific Aim 2. Model interactions between PC and metastatic sites using advanced microphysiological systems (MPS). MPS are populated entirely with human cells and recreate the architecture of the tumor (vasculature, stroma, solid tumor) and multicellular crosstalk of the tumor microenvironment. To determine the impact of the metastatic site on modulation of PC phenotypes and lineage switching the Modeling Core will perform experiments using MPS that recapitulate lymph node, liver and bone metastases. Specific Aim 3. Generate defined genomic alteration in LuCaP cells lines and/or other PC cell lines for detailed investigation of lineage plasticity. The Modeling Core will generate and distribute CRISPR engineered cell lines that express pathological mutations found in patient populations. These cells will be used for in vitro and in vivo investigations and in MPS to determine how these mutations contribute to lineage plasticity and treatment resistance. The Modeling Core is highly integrated with all three Projects and all Projects will rely significantly on the Core resources and expertise.