Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression

Cancer Cell. 2023 Aug 14;41(8):1407-1426.e9. doi: 10.1016/j.ccell.2023.06.005. Epub 2023 Jul 6.


Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1-6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and survival outcomes. Extensive stromal remodeling occurs in GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) is linked to aggressive phenotypes and poor survival, and SDC2 overexpression in CAFs contributes to tumor growth. Our study provides a high-resolution GAC TME atlas and underscores potential targets for further investigation.

Keywords: Cancer-associated fibroblast; Chronic Atrophic Gastritis; Ecotype; Gastric Adenocarcinoma; Immune-Stroma Crosstalk; Intestinal Metaplasia; Peritoneal Carcinomatosis; Single Cell RNA Sequencing; Syndecan 2; Tumor Microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma* / pathology
  • Cancer-Associated Fibroblasts* / pathology
  • Ecotype
  • Humans
  • Precancerous Conditions* / pathology
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism
  • Stromal Cells / pathology
  • Tumor Microenvironment