Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer

Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer

Cancer Discovery

10.1158/2159-8290.CD-21-0683

http://dx.doi.org/10.1158/2159-8290.cd-21-0683

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

oncology

08 March 2022

Kumar, V., Ramnarayanan, K., Sundar, R., Padmanabhan, N., Srivastava, S., Koiwa, M., Yasuda, T., Koh, V., Huang, K. K., Tay, S. T., Ho, S. W. T., Tan, A. L. K., Ishimoto, T., Kim, G., Shabbir, A., Chen, Q., Zhang, B., Xu, S., Lam, K.-P., … Tan, P. (2022). Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer. Cancer Discovery, 12(3), 670–691. https://doi.org/10.1158/2159-8290.cd-21-0683

Abstract 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. Significance: 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

Publisher Copyright

This research / project is supported by the National Research Foundation - National Research Foundation Singapore Fellowship
Grant Reference no. : NRF-NRFF2017-03

This research / project is supported by the National Medical Research Council - NMRC Transition Award
Grant Reference no. : NMRC/TA20Nov/0014

This research / project is supported by the Duke-¬NUS Medical School / A*STAR - Duke NUS Block funding
Grant Reference no. : N.A

This research / project is supported by the National Medical Research Council - Open Fund - Large Collaborative
Grant Reference no. : OF-LCG18May-0023

This research / project is supported by the National Medical Research Council - NCIS Centre Grant Research Core 3
Grant Reference no. : NR13NMR111OM

This research / project is supported by the National Medical Research Council - Singapore Translational Research (STaR)
Grant Reference no. : STaR/0026/2015

This research / project is supported by the National Medical Research Council / Ministry of Education - Research Centres of Excellence initiative
Grant Reference no. : CL2008-07

https://oar.a-star.edu.sg/communities-collections/articles/18305

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Institute of Molecular and Cell Biology