Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition
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
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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Research Article Gastroenterology Genetics Oncology

Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition

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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Figure 7

Kmt2c/d loss induces feedback upregulation of ribosomal protein expression due to inadequate translation.

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Kmt2c/d loss induces feedback upregulation of ribosomal protein express...
(A) GSEAs in scRNA-seq showing positive enrichment of gene sets associated with protein translation following Kmt2c/d deletion. (B) GSEAs in human TCGA STAD showing positive enrichment of gene sets associated with protein translation in KMT2C/D-LOF samples. (C) GSEAs in scRNA-seq showing negative enrichment of gene sets associated with protein translation following Pten deletion. (D) GSEAs in bulk RNA-seq of TY, TP, and TPCD stomach epithelial cells. Rapamycin suppressed the expression of mTORC1 target genes but upregulated expression of RPs. (E) H3K4me1 and H3K4me3 peaks and intensity at enhancers and promoters in TP and TPCD cells. The center line represents the median, the box limits represent the upper and lower quartiles, and the minimum and maximum whiskers represent the 5th and 95th percentiles, respectively. Statistical significance was determined using unpaired 2-tailed t test with Welch’s correction. (F) Z-score of 45 selected RP gene expression in bulk RNA-seq of TP and TPCD cells upon rapamycin treatment (10 nM, 24 hours). RP genes with identified promoter H3K4me3 peaks were included in the analysis. The center line represents the median, and the box limits represent the 5th and 95th percentiles, respectively. Statistical significance was determined using unpaired 2-tailed t test with Welch’s correction. (G) H3K4me3 signal change (log2 diff) between TP and TPCD cells. Promoter H3K4me3 peaks were categorized as upregulated (n = 264), downregulated (n = 409), unchanged (n = 8,872), and pooled RP genes (n = 54). The center line represents the median, the box limits represent the upper and lower quartiles, and the minimum and maximum whiskers represent the 5th and 95th percentiles, respectively. Statistical analysis was performed using 1-way ANOVA followed by Dunnett’s multiple comparisons test.