Common oral bacterium promotes tumor progression-associated activity in pancreatic cancer cells

Common oral bacterium promotes tumor progression-associated activity in pancreatic cancer cells

Virginia Tech researchers from the Department of Biomedical Engineering and Mechanics and the Department of Biochemistry have discovered a feature of a common oral bacterium that translocates to pancreatic cancer tumors that may aid in future therapeutic interventions for treatment. The bacterium Fusobacterium nucleatum may play a key role in how aggressively cancer grows and spreads throughout the body.

Pancreatic cancer is the third leading cause of cancer-related death in the United States. A particularly aggressive form of pancreatic cancer, pancreatic ductal adenocarcinoma, has a survival expectancy of less than six months.

Several features complicate the disease's treatment, including its ability to suppress the immune system and its complex location and structure, which make surgery and chemotherapy difficult to administer.

Scott Verbridge, associate professor of biomedical engineering and mechanics, and Barath Udayasuryan Ph.D. ’22, a graduate of the Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, conducted research on a bacterium found in, among other things, pancreatic cancer tumors. Most importantly, they discovered ways in which the bacterium can directly influence cancer progression and resistance to chemotherapy treatments.

These results are presented in the October 18 issue of Science Signaling.

Daniel J. Slade, associate professor of biochemistry and a leading expert on microbes in cancer and their biochemical interactions with the tumor microenvironment, also worked with Verbridge and Udayasuryan.

Verbridge's Integrative Tumor Ecology Laboratory has been collaborating with Slade's team on cancer research for years. Together they have made discoveries about the role of a particular microbe, F. nucleatum, in promoting cancer cell migration, particularly in colon cancer.

Because this microbe is a common oral bacterium, it has often been studied in connection with oral diseases such as periodontitis and gingivitis. However, little was known about how the microbe enters and adapts to tumor microenvironments, thereby increasing the aggressiveness of cancerous tumors. Other cancer research had confirmed the presence of the microbe in pancreatic cancer, leading Verbridge and his team to wonder whether this bacterium might also activate tumor migration in the pancreas.

“The tumor microbiome can influence cancer progression, so our goal is to better understand the role of these bacteria in cancer,” said Udayasuryan, who was named a 2022 Outstanding Doctoral Student in the College of Engineering at Virginia Tech Graduate School. "It was only in early 2022 that the tumor microbiome was overtly recognized as a hallmark of cancer. Cancer biology and infection biology have typically been viewed as separate fields of study, but the recent merger of the two fields is revealing fundamental insights into cancer progression. Our focus is on being at the forefront of this emerging paradigm, and we are at the cutting edge of research and looking at things that are yet to come no one had before.”

In the first analysis of the migration of infected pancreatic cancer cells, researchers encountered an unexpected hurdle: They found that the number of cells that migrated was difficult to quantify because the total number seemed to drastically exceed the cell population they expected in the system. Using in vitro tumor-on-a-chip models, Verbridge and his team confirmed that this microbe can bind to and invade pancreatic cancer cells, which then secrete molecules that stimulate accelerated growth of cancer cells. This finding explained why the team saw so many more cells than expected in their experiments. It also allowed them to identify an increase in the migration of infected cells.

In another important discovery, they found that the microbe can infect non-tumorous, normal pancreatic tissue cells. In their experiments, when a normal cell was infected, it continued to grow normally; However, its presence stimulated nearby cancer cells to grow and spread faster.

This new finding expands current ideas about noncancerous cells in and around tumor cells and how cancer spreads so aggressively. Any cell infected by the microbe could potentially be more susceptible to cancerous growth at a later date or even more susceptible to metastasis, which is how most cancers kill their hosts.

Armed with an understanding of how bacteria in tumors influence the growth and spread of cancer, scientists could develop more effective chemotherapy or immunotherapy treatments. These results may also help develop diagnostic and prognostic tools to detect cancer earlier.

Although we have shown that F. nucleatum is capable of driving pancreatic cancer cell proliferation and migration, we do not yet know the extent to which these results translate to living systems or human patients. These next steps will be important future work that could ultimately show us whether this knowledge could lead to more effective therapies tailored to a patient’s own microbiome components.”

Scott Verbridge, associate professor of biomedical engineering and mechanics

“Host-microbiome interactions are complex because many bacterial residents actually support human health and have been shown to improve the effectiveness of cancer treatments,” said Verbridge, who won a 2020 Engineering Dean’s Award for Research. “This makes my research very complex and meaningful,” Verbridge said. “There are still many questions, and as we search for answers we must be careful about how we might try to eliminate the harmful bugs that may share similarities with their more helpful relatives.”

Source:

Virginia Tech

Reference:

Udayasuryan, B., et al. (2022) Fusobacterium nucleatum induces proliferation and migration in pancreatic cancer cells through host autocrine and paracrine signaling. Scientific signaling. doi.org/10.1126/scisignal.abn4948.

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