Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer.
IF: 38.272
Cited by: 108


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. We profiled gastric malignancies at single-cell resolution and identified increased plasma cell proportions as a novel feature of diffuse-type tumors. We also uncovered distinct cancer-associated fibroblast subtypes with INHBA-FAP-high cell populations as predictors of poor clinical prognosis. Our findings highlight potential origins of deregulated cell states in the gastric tumor ecosystem. This article is highlighted in the In This Issue feature, p. 587.


Spatial Transcriptomics

MeSH terms

Cancer-Associated Fibroblasts
Single-Cell Analysis
Stomach Neoplasms
Tumor Microenvironment


Kumar, Vikrant
Ramnarayanan, Kalpana
Sundar, Raghav
Padmanabhan, Nisha
Srivastava, Supriya
Koiwa, Mayu
Yasuda, Tadahito
Koh, Vivien
Huang, Kie Kyon
Tay, Su Ting
Ho, Shamaine Wei Ting
Tan, Angie Lay Keng
Ishimoto, Takatsugu
Kim, Guowei
Shabbir, Asim
Chen, Qingfeng
Zhang, Biyan
Xu, Shengli
Lam, Kong-Peng
Lum, Huey Yew Jeffrey
Teh, Ming
Yong, Wei Peng
So, Jimmy Bok Yan
Tan, Patrick

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