Features of tumor cells and microenvironment associated with recurrence risk of mesenchymal-subtype gastric cancer based on bulk RNA-seq and scRNA-seq

Objective‍ ‍To analyze clinical characteristics of mesenchymal-subtype gastric cancer (Mes-GC) by integrating multi-omics data and explore the characteristics of tumor cells and microenvironment associated with the risk for recurrence. Methods‍ ‍Gastric tumor tissue samples were collected from the patients who visited Department of Gastroenterology of Army Medical Center of PLA from January 2022 to December 2023. Transcriptome and genome sequencing were applied for these tissue samples, including 19 cases of diffuse-type gastric cancer, 22 cases of intestinal-type gastric cancer, and 23 cases of mixed-type gastric cancer patients. Bioinformatics analysis was employed to investigate the differences in clinical characteristics and tumor microenvironment between Mes-GC and non-mesenchymal-subtype gastric cancer (non-Mes-GC) by integrating data resources including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and National Genomics Data Center (NGDC). Results‍ ‍Compared to non-Mes-GC patients, Mes-GC ones were characterized by later clinical stages, deeper tumor infiltration, and higher rates of lymph node metastasis. Kaplan-Meier survival analysis confirmed that Mes-GC patients were associated with shorter survival time, poor prognosis as well as increased risk of cancer recurrence （P<0.05）. Single-cell RNA sequencing data revealed that tumor cells in Mes-GC showed higher expression levels of the genes related to stemness, metastasis （P<0.05）, and epithelial-mesenchymal transition (EMT). And in the tumor microenvironment, there were significant more myeloid cells, smooth muscle cells, endothelial cells and fibroblasts, with the most pronounced elevation in the proportion of fibroblasts （P<0.05）. Moreover, the patients with larger proportion of fibroblasts were associated with poorer prognosis. Conclusion‍ ‍Mes-GC tumor cells exhibit higher stemness and EMT characteristics, and stromal cells such as myeloid cells, endothelial cells, and fibroblasts are enriched in the tumor microenvironment. These features may be key factors contributing to poor prognosis and high recurrence rate of Mes-GC.