LAUSR

We recently generated the first model of metastatic mixed-type gastric adenocarcinoma that closely recapitulates the human disease. Our model combines conditional loss of E-cadherin (Cdh1fl/fl) and p53 (Trp53fl/fl) with oncogenic Kras (KrasLSL-G12D/+) activation and yellow fluorescence protein (Rosa26LSL-YFP/LSL-YFP) expression in cells of the gastric parietal cell lineage (Atp4b-Cre). Median survival is 76.5 days (range 64-91 days, SD 7.2) with all mice developing local lymph node metastases and lung metastases, half developing paratracheal lymph node metastases, and 20% developing liver metastases. We previously provided proof of concept for the preclinical utility of our model by demonstrating extended survival upon treatment with a MEK inhibitor (PD0325901). Here we demonstrate the utility of this model to investigate the role of the microbiome in gastric carcinogenesis and to determine the use of circulating tumor cells (CTCs) as biomarkers of metastatic disease. The specific pathogen H. pylori is known to be causal in gastric adenocarcinoma. Further, many studies have implicated the microbiome in colon carcinogenesis. However, no studies have investigated the role of the normal microbiome in gastric carcinogenesis in the absence of H. pylori infection. We treated our model of mixed-type gastric adenocarcinoma with a commonly utilized antibiotic cocktail to deplete the gut microbiota and confirmed depletion of the microbiota by qPCR in stomach and fecal contents at necropsy. Microbiome depletion resulted in a 7.5-day increase in median survival (n=6) over vehicle treated mice (n=5, p=0.04). These data suggest a role for the normal microbiota in gastric cancer progression regardless of H. pylori infection. Given the broadly metastatic phenotype of our model, we examined whether the number of CTCs correlated with metastatic burden. Because our gastric cancer model incorporated a yellow fluorescence protein (YFP) as a marker of tumor cells, we used flow cytometry to measure CTCs in cardiac blood samples from terminal mice. We detected CTCs (defined as DAPI-;CD45-;YFP+) in all terminal mice and correlated CTC counts with lung metastatic burden. Mice with macrometastatic disease in the lung had >90 CTCs per 100 μl blood (n=3) as compared to mice with micrometastatic disease of the lung which showed Citation Format: Jacob Till, Prince Addai, Neha Bhagwat, Stephanie Yee, Erica Carpenter, Sam Yoon, Sandra Ryeom. A new mouse model of gastric adenocarcinoma: A valuable tool for preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4077.