Human Pre-Cancer Models

PROJECT SUMMARY/ABSTRACT Core 2: Human Pre-Cancer Models (HPM) Core The Human Pre-Cancer Models (HPM) Core will serve as a central repository for generation, propagation, and characterization of pre-cancer colonic organoids and isolation of neutrophils and patient-matched cytotoxic/CD8+ T cells as well as providing technical expertise to conduct key experiments. The HPM Core will provide support

to all three projects and interact closely with the Quantitative Biosciences (QB) Core. The HPM Core’s resource building will facilitate proposed projects and hypothesis generation for future pilot and feasibility studies. During subsequent years of the grant, larger collaborative efforts (within TBEL and elsewhere) will be supported

by the HPM Core as capability and expertise expand. The HPM Core will leverage existing, institutionally- supported infrastructure and equipment to provide a full range of fully-annotated human colonic organoids (normal, SSL, and adenoma). All the organoids in these studies will have an extensive record of participant

information and whole-exome sequencing (WES) along with matched germline DNA. The HPM Core will leverage resources from COLON MAP for acquisition of pre-cancer specimens and experience from the GI SPORE projects where we have established preclinical models of colorectal cancer (CRC) including patient-

derived CRC xenografts (PDXs) and organoids (PDOs). The HPM Core is established to support the overall goal of the TBEL application in determining how the microenvironment of colonic pre-cancer lesions is shaped by its individual components (epithelial, microbial, stroma, and immune cells). The HPM Core will coordinate efforts, consolidate resources, and share experimental

expertise by pursuing three Specific Aims: 1) generate and characterize epithelial, stromal, and microbial components of pre-cancer lesions; 2) establish culture and co-culture conditions of epithelial cells with colibactin- producing E. coli and immune and/or stromal components; and 3) manipulate colonic organoids via genetic and

pharmacologic perturbations. The immediate goal of the HPM Core is to provide support to all three of our projects and QB core. Core personnel will work closely with project and core leaders to ensure effective support and two-way communication. The longer-term goal of the HPM Core is the wider dissemination of these resources and expertise as we

welcome the opportunity to provide support to other TBEL recipients.