How chief cells modulate micro-niche during gastric carcinogenesis.
Haengdueng Jeong1,
1Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
Gastric carcinogenesis is a stepwise process; however, the molecular mechanisms that drive each stage
remain incompletely understood. Recent advances in lineage-tracing models and organoid systems have
provided compelling evidence that adult gastric stem cells (ASCs) and stem-like progenitor populations
serve as the primary cells of origin for tumor initiation. Among these, gastric chief cells function as
“reserve stem cells” that contribute to tissue regeneration by undergoing transdifferentiation into stemlike
metaplastic cells upon injury. This process is further reinforced by additional genetic alterations
and the supportive microenvironment, including macrophages, innate lymphoid cells, and cancerassociated
fibroblasts. Here, we employed epithelial organoid systems and in vivo mouse models to
dissect the stepwise molecular events underlying gastric carcinogenesis. Our findings demonstrate that,
in response to injury, chief cells rapidly secrete WFDC2, which induces IL-33 expression in adjacent
pit cells. This epithelial crosstalk subsequently activates M2 macrophages, thereby promoting
metaplastic progression. Furthermore, metaplastic chief cells exhibit increased expression of IL-17RA,
suggesting their responsiveness to inflammatory cytokine signaling within the niche.
Collectively, our results reveal that epithelial cells are not merely passive targets of transformation but
actively remodel the surrounding microenvironment to facilitate disease progression. These findings
provide mechanistic insight into how epithelial–micro-niche interactions drive the early stages of gastric
carcinogenesis.
