期刊
CANCER DISCOVERY
卷 12, 期 3, 页码 670-691出版社
AMER ASSOC CANCER RESEARCH
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资金
- NMRC, Singapore [NMRC/Fellowship/0059/2018, MOH-000627]
- Duke-NUS Medical School
- Biomedical Research Council, Agency for Science, Technology and Research
- NMRC [NR13NMR111OM, NMRC/STaR/0026/2015, MOH-OFLCG18May-0003]
- Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore
- Singapore Ministry of Education Research Centres of Excellence initiative
This study generated a comprehensive single-cell atlas of gastric cancer, providing molecular insights into the intra- and interpatient lineage states across distinct subtypes. The findings are important for understanding gastric cancer heterogeneity and developing relevant therapeutic strategies.
Gastric cancer heterogeneity represents a barrier to disease management. We generated a comprehensive single-cell atlas of gastric cancer (>200,000 cells) comprising 48 samples from 31 patients across clinical stages and histologic subtypes. We identified 34 distinct cell-lineage states including novel rare cell populations. Many lineage states exhibited distinct cancer-associated expression profiles. individually contributing to a combined tumor-wide molecular collage. We observed increased plasma cell proportions in diffuse-type tumors associated with epithelial resident KLF2 and stage-wise accrual of cancer-associated fibroblast subpopulations marked by high INHBA and FAP coexpression. Single-cell comparisons between patient-derived organoids (PDO) and primary tumors highlighted inter- and intralineage similarities and differences, demarcating molecular boundaries of PDOs as experimental models. We complemented these findings by spatial transcriptomics, orthogonal validation in independent bulk RNA-sequencing cohorts, and functional demonstration using in vitro and in vivo models. Our results provide a high-resolution molecular resource of intra- and interpatient lineage states across distinct gastric cancer subtypes.
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