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Integrative single-cell multiomics analyses dissect molecular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer

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National Science Review 2023年第6期10卷 96-107页

作者： Shuhui Bian Yicheng Wang Yuan Zhou Wendong Wang Limei Guo Lu Wen Wei Fu Xin Zhou Fuchou Tang Biomedical Pioneering Innovation Center School of Life Sciences Department of General Surgery Third Hospital Peking University State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical University Beijing Advanced Innovation Center for Genomics (ICG) Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Department of Pathology Peking University Third Hospital School of Basic Medical Science Peking University Health Science Center Peking University Third Hospital Cancer Center Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary Studies Peking University

Human gastric cancer is a highly lethal disease,but the underlying multiomic mole cular signatures remain largely uncle ar.Here,we performed multi-regional sampling,parallel single-cell multiomics sequencing and integrated analyses of human gastric cancer.We identified common transcrip tomic alterations of gastric cancer cells,such as aberrant down-regulation of genes associated with normal stomach function and up-regulation of KRT7,PI3,S100A4,etc.Surprisingly,aberrant and prevalent up-regulation of genes highly expressed in normal colorectal epithelial cells were also identified in cancer cells,which maybe partially regulated by promoter chromatin accessibility and DNA methylation levels.We reve aled the single-cell DNA methylome landscape of gastric cancer,and identified candidate DNA methylation biomarkers,such as hypermethylated promoters of TMEM240 and HAGLROS,and hypomethylated promoters of TRPM2-AS and HRH1.Additionally,the relationships between genetic lineages,D NA methylation and transcriptomic clusters were systematically revealed at single-cell level.We showed that DNA methylation heterogeneities were mainly among different genetic lineages of cancer cells.Moreover,we found that D NA methylation levels of cancer cells with poorer differentiation states tend to be higher than those of cancer cells with better differentiation states in the primary tumor within the same patient,although still lower than in normal gastric epithelial cells.Cancer cells with poorer differentiation states also prevalently down-regulated MUC1 expression and immune-related pathways,and had poor infiltration of CD 8+T cells.Our study dissected the mole cular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer using integrative single-cell multiomics analyses.

关键词： gastric cancer single-cell multiomics analysis intratumoral heterogeneity tumor differentiation

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