Gastric cancer rarely develops overnight. Instead, chronic inflammation can trigger a series of changes in stomach tissue that progress from normal cells to precancerous lesions and eventually to cancer. But where the mystery lies is why do some precancerous lesions develop into cancer while others do not? 

A new study from Eunyoung Choi, PhD, and colleagues helps answer that question by identifying the cancer-associated transcription factor SOX9 as a critical factor in the progression of spasmolytic polypeptide-expressing metaplasia (SPEM), a cell type increasingly recognized as a precursor to gastric cancer. The research was published July 14 in the journal Gastroenterology.

“Normal gastric chief cells transition into SPEM cells, which are associated both with mucosal recovery and cancer development,” said Choi, Associate Professor of Surgery and holder of the Naji N. Abumrad Chair. “Although SPEM has been recognized for years, the mechanisms regulating its progression have remained unclear.”

During chronic gastric injury, mature gastric chief cells can transform into SPEM cells as part of the stomach’s repair process. While this response may initially be protective, persistent inflammation and cancer-promoting signals can cause these cells to acquire characteristics associated with cancer development.

To investigate SOX9’s role in this process, researchers used two mouse models of gastric injury and carcinogenesis along with human gastric tissue samples. They found that SOX9 is required for chief cells to transition into SPEM cells following both acute and chronic injury.

When the researchers genetically removed SOX9, metaplasia failed to develop. The loss of SOX9 also prevented progression toward cancer and allowed repair-associated progenitor cells to return to a more normal state.

“These findings suggest that SOX9 functions as a master regulator of the cellular plasticity that drives gastric cancer development,” Choi said.

The study also revealed that SOX9-dependent SPEM cells help recruit fibroblasts to the base of gastric glands, contributing to a tissue environment that supports tumor formation.

Additionally, investigators identified a distinct subgroup of SPEM cells that express TOP2A, a protein associated with cell proliferation. Human tissue analyses showed that cells positive for both SOX9 and TOP2A were linked to metaplastic progression, suggesting these markers may help identify precancerous lesions at greater risk of becoming cancerous.

The findings may have important implications for patient care.

“Finding metaplasia on a biopsy is relatively common, but predicting which lesions will progress to cancer has remained challenging,” Choi said. “SOX9 and TOP2A positivity along with other SPEM cell markers may help identify patients with a higher likelihood of progression.”

Beyond their potential use as biomarkers, the results also point to new therapeutic possibilities. Targeting the cellular pathways regulated by SOX9 could provide an opportunity to interrupt the cancer development process before invasive disease occurs.

The researchers concluded that SOX9 is a critical regulator of SPEM development, metaplastic progression and gastric carcinogenesis. Future studies will explore how these findings can be translated into improved risk assessment tools and preventive strategies for patients at risk for gastric cancer.

The paper’s first author was Alexis Guenther, a graduate student in Cell and Developmental Biology in the Choi lab. Other Vanderbilt co-authors were Amanda Ruelas, Brianna Caldwell, MBA, Youngwon Cho, PhD, Changqing Zhang, Judith Romero-Gallo, MS, and Richard Peek, MD.

The study was supported in part by the National Institutes of Health (grants F31CA284715, R37CA244970, R01CA272687, R01CA077955, P01CA116087, R01DK058587, R01CA281732 and P20GM121322), the American Gastroenterological Association Research Foundation, the U.S. Department of Defense, and the Vanderbilt University School of Medicine Stanley Cohen Innovation Fund.

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Eunyoung Choi, PhD, associate professor of Surgery and of Cell and Developmental Biology is the recipient of the Young Investigator Award in Basic Science from the American Gastroenterological Association (AGA). 

Each year, the AGA honors two early-career investigators, one in basic science and one in clinical science, for their research achievements. The honorees must have held an academic faculty position for less than seven years. 

The AGA honored Choi for her work defining key oncogenes critical to gastric carcinogenesis, and for identifying potential drug candidates to target gastric precancerous stem cells. Choi specializes in the cellular mechanisms that drive the evolution of precancerous cells in gastric cancer and has pioneered the use of transgenic animal and precancer organoid models. 

An active AGA member, she serves as an abstract reviewer and council member for the AGA Council Cellular & Molecular Gastroenterology Section. Her accolades include the NIH/NCI Outstanding MERIT Award and the AGA-R. Robert & Sally Funderburg Research Award in Gastric Cancer, American Association for Cancer Research-Debbie’s Dream Foundation Innovation Grant, and the Vanderbilt University Stanley Cohen Innovation Fund Award. 

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