Abstract
Based on the observation that loss-of-function mutations of KMT2C and KMT2D (KMT2C/D) are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models (GEMMs) to conditionally knock out Kmt2c and Kmt2d in gastric epithelial cells. We observed that Kmt2c/d loss led to nuclear dysplasia, cellular crowding, and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks after Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human intestinal-type gastric adenocarcinoma. Bioinformatic integration of single-cell RNA-seq of our GEMMs and human gastric cancer datasets showed coclustering of normal and of cancerous gastric epithelial cells. Kmt2c/d knockout in gastric epithelium reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering the cells hypersensitive to mTOR complex 1 (mTORC1) inhibitors. Additionally, Kmt2c/d knockout increased MHC class I molecule expression and enhanced antigen presentation. Combination of mTORC1 inhibition and anti–programmed cell death 1 immunotherapy markedly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c/d loss in gastric cancer initiation and suggest potential therapeutic strategies for KMT2C/D-deficient gastric cancer.
Authors
Naitao Wang, Dan Li, Tao Zhang, Mohini R. Pachai, Dana M. Schoeps, Yudi Bao, Woo Hyun Cho, Makhzuna N. Khudoynazarova, Kae Kristoff, Marion Liu, Laura Tang, Yelena Y. Janjigian, Ping Chi, Yu Chen
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ISSN: 0021-9738 (print), 1558-8238 (online)