Abstract 4339: Single cell RNA sequencing dissects cellular growth factor dependencies and oncogenic driver effects in an organoid model of gastric cancer

Abstract

Abstract Gastric cancer is a lethal malignancy with few therapeutic options. Gastric tumors rely on complex intercellular signaling “crosstalk” that enables tumor development, metastasis, and therapeutic resistance. To recapitulate the intercellular communications among various cell populations that exist in vivo, we are using a three-dimensional culture system to grow and manipulate mouse gastric tissue in vitro, otherwise referred to as organoids. Importantly, this organoid model contains epithelium with its endogenous mesenchymal niche and does not require exogenous Wnt stimulation. To systematically analyze the distinct cellular lineages and their interactions, we applied a massively-scaled single cell RNA-Seq platform to sequence thousands of individual cells from organoid cultures. With PCA and t-SNE analysis of the high-dimensional data generated from single cell RNA-seq, we characterized two major cell types, i.e. epithelial and mesenchymal cells. Leverage the information from single cell transcriptome profiles, we identified specific niche factors of the Wnt signaling pathways that are activated in different stomach cell lineages. These results suggest that the mesenchymal cell populations provide a potential source of the R-spondin, a Wnt agonist, that sustains the growth of epithelium. Furthermore, we compared cell populations from Cdh1-/-/Trp53-/- and Trp53-/-organoids, and characterized changes on the transcriptome profiles due to the loss of Cdh1, an early oncogenic event in diffuse gastric cancer development. Overall, using organoid model and high-throughput single cell RNA-Seq provides a novel approach to study early tumor transformation and critical cancer-stroma interactions. Citation Format: Jiamin Chen, Noemi Andor, Susan M. Grimes, Billy Lau, Hanlee P. Ji. Single cell RNA sequencing dissects cellular growth factor dependencies and oncogenic driver effects in an organoid model of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4339. doi:10.1158/1538-7445.AM2017-4339