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

Shuhui Bian; Yicheng Wang; Yuan Zhou; Wendong Wang; Limei Guo; Lu Wen; Wei Fu; Xin Zhou; Fuchou Tang

doi:10.1093/nsr/nwad094

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

Natl Sci Rev. 2023 Apr 11;10(6):nwad094. doi: 10.1093/nsr/nwad094. eCollection 2023 Jun.

Authors

Shuhui Bian^{1

2

3}, Yicheng Wang^{1

4}, Yuan Zhou^{1

4}, Wendong Wang¹, Limei Guo⁵, Lu Wen^{1

4}, Wei Fu^{1

6}, Xin Zhou^{1

6}, Fuchou Tang^{1

4

7}

Affiliations

¹ Biomedical Pioneering Innovation Center, School of Life Sciences, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China.
² State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China.
³ Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
⁴ Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.
⁵ Department of Pathology, Peking University Third Hospital, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China.
⁶ Peking University Third Hospital Cancer Center, Beijing 100191, China.
⁷ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.

Abstract

Human gastric cancer is a highly lethal disease, but the underlying multiomic molecular signatures remain largely unclear. Here, we performed multi-regional sampling, parallel single-cell multiomics sequencing and integrated analyses of human gastric cancer. We identified common transcriptomic 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 may be partially regulated by promoter chromatin accessibility and DNA methylation levels. We revealed 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, DNA 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 DNA 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 CD8⁺ T cells. Our study dissected the molecular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer using integrative single-cell multiomics analyses.

Keywords: gastric cancer; intratumoral heterogeneity; single-cell multiomics analysis; tumor differentiation.