Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2022
- Source ID
- 10.1158/2159-8290.cd-21-0683
Entities
People
- Angie Lay Keng Tan
- Asim Shabbir
- Biyan Zhang
- Guowei Kim
- Huey Yew Jeffrey Lum
- Jimmy So
- Kalpana Ramnarayanan
- Kie Kyon Huang
- Kong-Peng Lam
- Mayu Koiwa
- Ming Teh
- Nisha Padmanabhan
- Patrick Tan
- Qingfeng Chen
- Raghav Sundar
- Shamaine Wei Ting Ho
- Shengli Xu
- Su Ting Tay
- Supriya Srivastava
- Tadahito Yasuda
- Takatsugu Ishimoto
- Vikrant Kumar
- Vivien Koh
- Wei Peng Yong
Organizations
- Agency for Science, Technology and Research
- Duke–NUS Medical School
- Kumamoto University
- Nanyang Technological University
- National University Health System
- Naval Medical Research Center
- Yong Loo Lin School of Medicine