Project Summary: Organoids Core Multiple studies support the ability of organoids to faithfully retain the biological characteristics of the tissues from which they are derived, thus offering a unique system for molecular target discovery and development. Importantly, patient-derived organoids (PDOs) retain the drug responses seen in the original patient, indicating that organoid culture conditions maintain the target profile and signaling networks of the originating tissue. Organoids also have the advantage that they can be genetically manipulated for target modulation and can be grown as xenografts that histologically mirror the originating normal or tumor tissue for both in vitro and in vivo testing. Based on these strengths, an Organoid Core is proposed for Phase 2 of the CMTDD COBRE. This Core, which builds on the success of the organoid component of the Phase 1 Target Validation Core, is specifically designed to facilitate the use of organoids by CMTDD investigators and the wider research community. Organoid-based research requires an established infrastructure, considerable expertise, and a substantial commitment of time and resources; therefore, there are significant barriers to the adoption of organoid systems by individual laboratories. By establishing organoids, as well as providing expertise, resources, reagents and training, the Core will remove these barriers to the use of these valuable model systems. The Core currently holds normal and tumor PDOs from colon, rectum and small intestine, liver, breast, pancreas and prostate as well as organoids from a number of mouse models, and plans to expand to additional tissues and diseases as demand is identified. This biobank of normal and disease organoids from multiple tissues represents a valuable resource for the research community at large. PDOs in the Core are associated with deidentified clinical data and will be genetically characterized, which will aid in identification of suitable models for hypothesis testing. The utility of the model on which the Core is built is evident from our track record under Phase 1. We have an expanding biobank of patient and mouse-derived organoids and have established techniques for genetic manipulation (e.g., transfection, CRISPR/Cas9-mediated knockout), drug/toxicity testing, and biochemical and histological analysis of organoids. The core has supported research in multiple laboratories and efforts under Phase 1 have contributed to both publications and successful grant applications. Based on the experience gained in Phase 1, the overall goal of the Organoid Core will be to develop a large repository of extensively characterized organoids for use by COBRE investigators and the wider research community and to lend expertise and reagents to promote and support the use of these structures. To accomplish this goal, the Organoid Core will coordinate with other Center Cores and CMTDD investigators to pursue three Specific Aims: (1) To expand and further char...