Helicobacter pylori cancer associated CagA protein drives intestinal metaplastic transition in human gastric organoids

Abstract

Gastric intestinal metaplasia (GIM) constitutes a pre-neoplastic stage in the development of stomach cancer. While strong evidence points to a role of infection with CagA positive Helicobacter pylori in the development of GIM, currently available experimental models have not provided mechanistic clues on this association. Here, we ectopically expressed the H. pylori CagA protein in human gastric organoids derived from normal, primary epithelial cells. Native CagA protein was produced and rapidly processed to yield a tyrosine-phosphorylated C-terminal fragment of [~]35 kDa. It led to an activation of the STAT3 pathway and aberrant elevation of CDX2 expression, a marker of intestinal type of cells, as well as other intestinal markers. Thus, CagA drives re-programming of gastric cells towards an intestinal-like phenotype, towards GIM. In summary, we describe a cooperative mechanism of CagA-induced STAT3 signaling and intestinal-like trans-differentiation, promoting a pre-neoplastic state. Our model provides mechanistic evidence for a direct role of CagA in driving premalignancy in gastric pathogenesis.