Deep inside the stomachs of an estimated half of the worlds population lurks a bacterium known as Helicobacter pylori, a bug that means business. While many people are infected and never even know, in some cases chronic H. pylori infections predispose individuals to develop gastric (stomach) cancer, the fifth most common cancer type worldwide. The Salama Lab in the Human Biology Division at Fred Hutchinson Cancer Center has built its reputation studying this enigmatic bug, focusing on the bacterium, the host, and everything in between. A recent study from the labpublished in Cancer Research Communications and helmed by former postdoc Dr. Valerie OBrientakes the team into uncharted territory and promises a greater understanding of how H. pylori promotes gastric disease.

In order to understand the relationship between H. pylori and gastric cancer, explains Dr. Salama, its important to distinguish between the tissue inflammation that H. pylori causes and the development of gastric cancer. Indeed, the link between inflammation and carcinogenesis in the stomach is complicatedinflammation isnt strictly required for gastric cancer to develop, and many patients with stomach inflammation wont develop gastric cancer. To better clarify this relationship, Drs. OBrien and Salama turned to an innovative transgenic mouse model in which an oncogenic KRAS protein is artificially expressed the stomachs chief cells (the cells which produce and secrete digestive enzymes), which causes gastric dysplasia similar to what is seen in human patients prior to the development of gastric cancer. In what was a surprising finding, the team discovered that H. pylori-driven inflammation synergizes with oncogenic KRAS to worsen gastric dysplasia in these mice. This suggested that H. pylori may not merely plant the seeds of gastric cancer, but may also provide fertile ground for those seeds to grow. However, one big question remained: was H. pylori simply accelerating disease progression in these mice, or was it causing a different disease trajectory altogether?

In their most recent publication, Dr. OBrien and colleagues address this question by leveraging state-of-the-art single cell RNA sequencing (scRNA-seq) of stomach tissue from KRAS-expressing mice with or without concurrent H. pylori infection. By clustering cell types based on the expression of different marker genes and comparing these cell types between conditions, the team found that the combination of oncogenic KRAS expression and H. pylori infection resulted in the expansion of a specific type of pit cell (a different cell type found in the stomach lining) expressing a gene called Muc4. Importantly, they found very few Muc4-expressing pit cells in mice with oncogenic KRAS expression or H. pylori infection alone. Whats more, they found that expansion of these Muc4-expressing pit cells requires H. pylori-driven gastric inflammation and that these cells also express amphiregulin, an epithelial cell protein involved in cell growth and wound healing. But is any of this relevant to gastric cancers in patients? Strikingly, it appears soOBrien and colleagues found MUC4-expressing pit cells in human gastric cancer tissue samples, where they appear to increase in number over the course of disease progression and co-express markers of high cell proliferation. Future work will test whether this cell type helps drive active disease.

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A new cell type with links to gastric cancer steps up for its mugshot - Fred Hutch News Service