Mouse Model and Pathological Analysis Core

CORE 2 - MOUSE MODELS AND PATHOLOGICAL ANALYSIS CORE: SUMMARY The purpose of Core 2 is to support the research of each of the projects in the ELEVATE program project grant (PPG) by providing access to uniform mouse models of hepatocellular carcinoma (HCC) and high-quality human HCC tumor tissues and patient blood samples and by providing pathological analysis of both mouse and human tumor specimens. This Core is co-directed by two investigators who bring expertise in mouse models of cancer (Dr. Windle) and in oncologic pathology (Dr. Idowu), and the core benefits from the capabilities and resources available in the Virginia Commonwealth University/Massey Cancer Center Transgenic/Knockout Mouse Core and the Tissue and Data Acquisition and Analysis Core, directed by Drs. Windle and Idowu, respectively. The primary function of the Mouse Models component of Core 2 will be to generate and provide experimental animals of three sophisticated mouse models of HCC, including 1) DIAMOND/AAV-PNPLA3I148M mice, which develop NAFLD, NASH, and HCC in response to a high-fat/high- sugar “Western diet”; 2) an orthotopic mouse model of HCC/NASH; 3) a Sleeping Beauty-Hydrodynamic Tail Vein Injection (SB-HDTV) model, in which administration of plasmids encoding MYC alone or in combination with other oncogenes results in efficient HCC formation; and 4) the DEN/CCl4 model in which treatment with a potent hepatocarcinogen regimen results in reproducible HCC development. Because these models require a degree of technical expertise and extensive oversight during production, centralizing their production in a core will enhance both consistency and efficiency across the ELEVATE program. The functions of the Pathological Analysis component of Core 2 are two-fold: 1) to provide ready access to high-quality, de-identified frozen and formalin-fixed paraffin-embedded human HCC tumor specimens with accompanying demographic, clinical, histopathological, and molecular annotation, as well as patient blood samples; and 2) to perform pathological analysis/interpretation of both mouse and human liver and tumor samples. Centralizing the pathological analysis will provide for consistency in pathological read-outs across projects. Through the provision of high- quality reagents (experimental animals or human tumor and tissue specimens) and services, Core 2 will enhance both integration across the projects as well as the rigor and reproducibility of the resulting science generated from this PPG.