Single-cell transcriptomic profiling uncovers cellular complexity and microenvironment in gastric tumorigenesis associated with Helicobacter pylori

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Abstract Background Helicobacter pylori (H. pylori) infection is a key initiating factor in the Correa cascade of gastric carcinogenesis, but the comprehensive understanding of the pathogenic mechanisms underlying H. pylori -induced gastric cancer (GC) remains elusive. Here, we generated a single-cell atlas of gastric tumorigenesis comprising 18 specimens of gastritis, intestinal metaplasia and GC with or without H. pylori infection. Results Gradually decreased proportion of epithelial cells and increased percentages of myeloid cells were observed in Correa carcinogenic cascade. Remarkably, the epithelial subset enterocytes were highly enriched in intestinal metaplasia, with high expression of lipid metabolism-related genes, and HNF4G was predicted as its specific transcription factor. Compared to non-cancerous tissues, GC exhibited completely different fibroblast cell states, with enrichment of immune regulatory functions. Furthermore, the differentially expressed genes, in H. pylori-positive and negative epithelial cells, fibroblasts and myeloid cells, were identified. Notably,the stromal cells, particularly inflammatory-cancer associated fibroblasts (iCAFs) and tumor-like Endothelial cells (ECs), play an important contributory role in GC microenvironment. H. pylori-positive specimens exhibited enriched cell-cell communication, with significantly active SPP1, TNF signaling networks. Conclusions Our study provides a comprehensive landscape of gastric carcinogenesis ecosystem and novel insights into the molecular mechanisms underlying H. pylori-induced GC.

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