Single-cell multi-omics analysis reveals the plasticity of isthmus stem cells in gastric carcinogenesis.

Gastric cancer remains one of the most lethal and prevalent malignancies, yet the cellular composition and developmental trajectory of its tumor populations are not fully understood. In this study, we performed single-cell multiome sequencing on paired tumor and adjacent tissue samples from gastric cancer patients. By integrating single-cell RNA sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) data, we identified three primary epithelial components in gastric cancer: normal cells, metaplastic cells and cancer cells. Our analysis revealed that gastric isthmus stem cells exist in three distinct states in the context of gastric cancer: normal isthmus stem cells, SI + metaplastic isthmus stem cells (SI: Sucrase-Isomaltase, NCBI gene ID: 6476, Ensembl ID: ENSG00000090402), and cancer isthmus stem cells. SI + metaplastic isthmus stem cells serve as the cellular origin of gastric intestinal metaplasia, while cancer isthmus stem cells give rise to heterogeneous subpopulations of cancer cells. Furthermore, somatic mutation analysis demonstrated that cancer cells are derived from metaplastic cells. Collectively, our findings reveal the important role of isthmus stem cells in gastric carcinogenesis, reconstruct the lineage trajectory and establish a refined classification system for gastric cancer cells.