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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An early-stage clinical trial, supported by the Department of Defense, has demonstrated that the targeted cancer drug trametinib shows potential as an interventional therapy to reprogram precancerous gastric lesions, potentially preventing them from becoming malignant, and that it can be administered safely.

The results of the Phase 1 trial involving 15 patients, which were published recently in Gastroenterology, were pleasantly surprising, said James Goldenring, MD, PhD, professor of Surgery and of Cell and Developmental Biology at Vanderbilt University Medical Center.

The primary goal of this trial was to evaluate whether a low-dose, limited duration treatment of two weeks with trametinib would be safe for patients at risk for developing a second cancer after having undergone resection of a Stage 1 gastric cancer. The drug also showed promise that it could be the first therapeutic intervention against precancerous lesions in the stomach.

Endoscopies revealed that trametinib reversed metaplasia, which is an abnormal change of cells into ones that are non-native to the tissue and can progress to dysplasia, an irreversible change in cell development that can lead to cancer. While the 15 patients in the study had no evidence of recurrent cancer, they did have extensive metaplasia when they entered the study.

“I was pleasantly surprised at how much benefit we could see in the endoscopies after one month and one year; it really was pretty remarkable,” said Goldenring, the Paul W. Sanger Professor of Experimental Surgery.

The reversal of the metaplasia could be viewed in endoscopic images and was confirmed with biopsies.

“I think that’s almost more compelling than anything else in this study,” Goldenring said. “I honestly did not expect endoscopies to be that different, but they were.”

However, he noted that follow-up clinical trials with more participants are needed to further validate the drug’s efficacy. The only significant side effect among the participants was one patient with a mild increase in blood pressure after trametinib treatment that returned to normal after the patient stopped taking the drug.

The patients in the study were recruited from Japan, where the clinical trial was led by Sachiyo Nomura, MD, PhD, in collaboration with Goldenring. Trametinib is an inhibitor of the MEK signaling pathway. MEK, an abbreviation for the mitogen-activated extracellular signal-regulated kinase pathway, plays an integral role in the development of stomach cancer.

The study was supported by a $2.5 million Department of Defense Translational Team Science Award, which is also supporting another clinical trial in the United States with similar aims. The U.S. clinical trial will evaluate the effectiveness of pyrvinium, an existing medicine that has been used for the past 70 years to treat pinworms in children, for a new purpose — reversing metaplasia of stomach cells and killing dysplastic precancerous cells. Pyrvinium also blocks the MEK pathway.

While stomach cancer is one of the three leading causes of cancer-related deaths worldwide, its incidence is lower is the U.S. Nevertheless, it does occur more frequently among minority ethnic groups, and incidence has been rising among young women. DOD support for clinical trials reflects the increased incidence of stomach cancer in minority groups, which make up a higher percentage of the U.S. armed services than of the general population. In the U.S., most stomach cancers are diagnosed at late stages when they are more difficult to treat.

Goldenring said he hopes the MEK inhibitor study will spur more research into therapeutic interventions for people with precancerous lesions who are at high risk for cancer.

“I’m hoping that this is a direction that multiple researchers might take in the future to really change the dynamics of how we’re going to intervene so that people don’t develop cancer,” he said. “That’s a different mindset than we’ve had previously.”

Eunyoung Choi, PhD, associate professor of Surgery and of Cell and Developmental Biology, is a co-principal investigator of the pyrvinium study along with Katherine Garman, MD, associate professor of Medicine at Duke University. Choi is also a co-author of the study published in Gastroenterology.

Goldenring is supported by grants from the Department of Defense, a Department of Veterans Affairs Merit Review Award, and the National Institutes of Health (R01DK101332 and R01CA272687. Choi is supported by grants from the National Institutes of Health (R37CA244970 and R01CA272687), the Department of Defense, the American Association for Cancer Research, and an American Gastroenterological Association Robert & Sally Funderburg Research Award.

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