Dissecting the differentiation origins of intestinal metaplasia and early intestinal-type gastric cancer in gastric antrum by single-cell RNA profiling

Intestinal-type gastric cancer (IGC) is associated with a multi-step carcinogenic process, comprising non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, and gastric dysplasia. The risk of developing IGC gradually increases as the disease progresses. However, the origin of cell differentiation and its carcinogenic potential in different stages of gastric disease remains poorly understood. To address this issue, we analyzed the differentiation trajectory of epithelial cells in different disease stages from gastric antrum biopsies in patients with precancerous lesions and early GC using single-cell sequencing data. Our findings revealed that progenitor cells (PCs) act as the ancestors of antral gland mucous cells (GMCs) and pit mucous cells (PMCs) in the NAG/CAG stage. In the IM stage, GMCs, as well as PCs, may acquire the ability to become intestinal-like stem cell phenotypes, eventually differentiating into mature enterocyte cells. Secretory progenitor cells may differentiate into pre-secretory cells and goblet cells. In the early IGC stage, KIAA0101 + PRAP1 + PCs may be the potential origin of early IGC. These findings provide valuable insights for further research into the molecular mechanisms underlying the development of IGC and may contribute to the development of novel prevention and treatment strategies.