Colorectal cancer is the second most common form of cancer in the world, with rates about 30 percent higher in developed countries. It’s expected to cause 51,020 deaths in the United States during 2019.

More than 15 percent of carcinomas can be attributed to known infectious agents, such as bacteria and viruses.

Daniel Slade, assistant professor in the Department of Biochemistry from the College of Agriculture and Life Sciences, and Scott Verbridge, associate professor in the Department of Biomedical Engineering and Mechanics in the College of Engineering, have received a $358,627 award from the National Institutes of Health (NIH) to better understand how an oral bacterium is involved in the proliferation of colorectal cancer.

Fusobacterium are gram-negative, anaerobic, opportunistic bacteria that are involved in multiple diseases and cancers. Fusobacterium nucleatum is linked to the accelerated progression and severity of colorectal cancer.

“We are beginning to uncover that Fusobacterium nucleatum is overrepresented in a variety of cancers, including colorectal, pancreatic, and esophageal, and that this bacterium potentially plays a role in disease severity and outcome,” said Slade, an affiliated faculty member of the Fralin Life Sciences Institute.

As far as Slade and Verbridge know, Fusobacterium nucleatum is not causing cancer, but seems to be acting as an accelerant.

“The bacteria can track to established oncogenic cells and influence the tumor directly by binding to the surface, thereby inducing inflammatory signaling. Basically, adding Fusobacterium to a tumor is like throwing gas onto a fire. The fire is already there, it’s just that the Fusobacterium nucleatum accelerates the cancer,” said Verbridge.

There are some phenotypes, or observable traits and characteristics, that bacteria and cancer cells share.

Metastasis is one that Slade and Verbridge are excited to explore. In metastasis, cancer cells spread by leaving the primary tumor and entering the blood vessels. Fusobacterium also spread throughout the blood stream. Seeing how these two interact with one another in the same vasculature highway is at the core of their research.

Using funding from this grant, the researchers will determine if F. nucleatum is able to “hitch a ride” with malignant cancer cells and if they are able to “drive” the migration of cancer cells throughout the body.

“The bigger question becomes: when the bacteria interact with the cancer cells, are the bacteria inducing these metastatic phenotypes? Are they changing how the tumor microenvironment responds? And can these bacteria directly induce signals that will be pro-metastatic in the presence of cancer cells?” asked Slade.

To  answer these questions, Slade and Verbridge are teaming up with Chang Lu, the Fred W. Bull Professor in the Department of Chemical Engineering in the College of Engineering, and Irving Coy Allen, associate professor in the Department of Biomedical Sciences and Pathobiology at the Virginia-Maryland College of Veterinary Medicine, to build a 3D microfluidic tissue model that will mimic the vasculature of a tumor.

Slade and Verbridge labs
Virginia Tech researchers studying how oral bacteria contributes to colorectal cancer include (from left to right) Ph.D. students Ariana Umaña and Blake Sanders, from the Slade lab; Assistant Professor Daniel Slade (back, center); Associate Professor Scott Verbridge; and Barath Udayasuryan (front, right), Ph.D. student in the Verbridge lab. Photo credit: Alex Crookshanks.

“What this grant is really going to allow us to do is to build more realistic and accurate tissue models. It’s not as involved or as expensive as mouse models of infection,” said Slade.

Creating this model is key to understanding how Fusobacterium are directly interacting with the endothelial cells of the blood vessels and the epithelial cells of tumors in an anaerobic environment. This controlled tissue system, also known as a “small microenvironment on a chip” can show researchers how the bacteria survive and disseminate in a tissue microenvironment.

To better understand the smaller, more complex changes that occur in the programming of infected cancer cells, researchers need to look even closer.

They are turning to epigenetic profiles, which allow them to observe the quick changes that affect the fundamental processes and instructions that are integrated in the DNA blueprint. To conduct these epigenetic studies, they will utilize microfluidic technologies that have been developed by Chang. “Looking at the epigenetic profiles, we can see if bacterial-induced changes in DNA methylation patterns changes key gene transcription and protein translations, and if those correspond to either cancer or pro-metastatic pathways,” said Slade.

If scientists are able to understand how the bacterium spreads throughout the body, and if it is involved in the metastasis of infected cancer cells, then they can define a potential course of action for treatment.

“If these Fusobacterium-infected cancer cells are problematic, then they are a novel target,” said Verbridge.

For the future, Slade hopes to look at nonantibiotic therapies that can put a halt to Fusobacterium-induced cancers. Some antibiotics, such as metronidazole, kill all anaerobic bacteria within the gut, even the ones that are critical to maintaining a healthy gut. If a therapy is created that can specifically target cancer-accelerating Fusobacterium, then the normal healthy gut flora can remain intact.

“These bacteria are the dark matter of health. There are significantly more of these in tumor tissues than we often appreciate, and I predict that we’ll continue to find new ways that these tissue-resident bacteria participate in a host of diseases,” said Verbridge.

Pilot studies for this research were funded by the Fralin Life Sciences Institute, as well as by multiple grants from the Institute for Critical Technology and Applied Science.

~Written by Kendall Daniels