Deciphering the Underpinnings of Stomach Cancer With the Help of an AACR Grant

Valerie O’Brien, PhD, is using her microbiology expertise to model and study gastric cancer development with early support from a Debbie’s Dream Foundation-AACR grant.

As a graduate student at Washington University in St. Louis, Valerie O’Brien, PhD, studied chronic bacterial infections. Then, an opportunity to donate bone marrow to a young boy with leukemia motivated her to shift her focus.

“That got me interested in cancer because I could see how it was such an important disease worldwide,” she recalled. “I was looking for a way to combine [my] expertise with cancer.”

Dr. O’Brien chose to pursue a postdoctoral fellowship in the lab of Nina Salama, PhD, a professor, senior vice president of education, and the Dr. Penny E. Petersen Memorial Chair for Lymphoma Research at the Fred Hutchinson Cancer Center in Seattle, who studies a bacterium called Helicobacter pylori (H. pylori), which infects the inner lining of the stomach. According to the National Cancer Institute (NCI), the bacterium can survive for long periods of time by neutralizing stomach acid, burrowing into the mucus that coats the inside of the stomach, and possibly blocking immune responses. 

Chronic infection with H. pylori leads to chronic inflammation, which can damage the stomach lining and drive cancer development. Worldwide, an estimated 80% of gastric cancer cases can be attributed to H. pylori, which disproportionately affects racial and ethnic minorities and people living in low- and middle-income countries.

However, funding for gastric cancer research is relatively limited, Dr. O’Brien said. Early in her fellowship, she was awarded the Debbie’s Dream Foundation-AACR Gastric Cancer Research Fellowship in memory of Sally Mandel, which offers research funding to gastric cancer investigators.

“The impact of an award like this early in my career is immeasurable,” Dr. O’Brien said shortly after receiving the grant in 2018. “This will allow me to make great progress on gastric cancer research, which will set me up to open my own independent research group and gain additional funding down the road.”

Dr. O’Brien used the grant to help her make a mouse model of H. pylori-driven gastric cancer. She hoped the model would allow her and her colleagues to better understand how H. pylori changes stomach cells at the molecular level, which could potentially identify detectable markers of gastric cancer and help researchers design new treatments.

“In gastric cancer, two of the biggest challenges are a lack of early detection in patients and a lack of good treatment options,” Dr. O’Brien said. “My research may be able to address one or both of these issues.”

In 2023, Dr. O’Brien published some of her progress in Cancer Research Communications. Researchers had previously observed that mice whose stomachs were engineered to express overactive copies of the cancer driver gene KRAS experienced cell changes indicative of precancer; infecting these mice with H. pylori made the changes more aggressive. To investigate the molecular underpinnings of these H. pylori-induced changes, Dr. O’Brien and colleagues performed single-cell RNA sequencing on stomach tissue from mice that did and did not express overactive KRAS and that were and were not infected with H. pylori.

They found that samples from KRAS-expressing, H. pylori-infected mice had an abundance of metaplastic pit cells that had replaced other types of stomach cells where they typically shouldn’t. These metaplastic pit cells showed a variety of gene expression patterns not characteristic of normal pit cells, including high expression of the genes MUC4 and amphiregulin, which can promote cell proliferation.

Indeed, in human samples of gastric cancer, pit cells that expressed MUC4 also expressed high levels of cell proliferation markers and were more abundant in samples representing later disease stages. 

Dr. O’Brien explained that the study was a solid start toward understanding how these metaplastic changes occur. “We still have much to learn about how and why H. pylori infection leads to gastric cancer,” she said in an AACR grantee update. “In our mouse model, metaplastic pit cells required H. pylori-driven inflammation, and I am particularly excited to investigate how the immune response to H. pylori may harm the stomach epithelium.”

Dr. O’Brien can now pursue this topic as an assistant professor of medicinal chemistry and molecular pharmacology at Purdue University, where she has started her own gastric cancer laboratory. The funding she received from the Debbie’s Dream Foundation-AACR Gastric Cancer Research Fellowship helped pave the way for her to receive a prestigious K99/R00 grant from the NCI of the National Institutes of Health, an outcome she wasn’t sure would have been possible otherwise.

“That’s why it’s so important to have organizations like AACR and Debbie’s Dream Foundation that are helping scientists like me so we can stay in the field of gastric research,” Dr. O’Brien said in 2018. “When I think about how I want my career to progress, I’m very interested in and passionate about gastric cancer, and this is an area that I would really love to stay in.”