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Single-cell Profiling Uncovers a Muc4-Expressing Metaplastic Gastric Cell Type Sustained by Helicobacter
Valerie P O'Brien1, Yuqi Kang1, Meera K Shenoy2
1Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington.
Cancer Research Communications
|September 7, 2023
Summary
Helicobacter pylori infection drives stomach cancer by promoting metaplastic pit cell expansion through inflammation. These cells, found in human gastric cancer, indicate an early step in cancer development.
Area of Science:
- Gastroenterology and Oncology
- Microbiology
- Cell Biology
Background:
- Mechanisms of Helicobacter pylori (Hp)-driven stomach cancer remain unclear.
- Hp infection and KRAS activation alter gastric metaplasia and increase inflammation.
Purpose of the Study:
- To investigate the role of metaplastic pit cells in Hp-driven gastric preneoplasia.
- To identify the cellular and molecular drivers of Hp-associated gastric cancer.
Main Methods:
- Utilized a transgenic mouse model with Hp infection and KRAS activation.
- Employed single-cell RNA sequencing, flow cytometry, and immunohistochemistry.
- Analyzed human gastric cancer samples for MUC4 expression.
Main Results:
- Hp+KRAS+ mice developed a metaplastic pit cell population expressing MUC4 and amphiregulin.
- Metaplastic pit cells were linked to macrophage and T-cell inflammation.
- Cell expansion was dependent on Hp-driven inflammation and reversed by Hp eradication.
- MUC4 expression correlated with proliferation in human gastric cancer.
Conclusions:
- Identified Hp-associated metaplastic pit cells as a precancerous lineage.
- Hp-driven inflammation promotes expansion of these cells, contributing to gastric cancer.
- Metaplastic pit cells represent an early step in the gastric metaplasia-to-cancer cascade.
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