How Little Critters Reveal Clues About Cancer

There are more microorganisms in the world than we can count, and just a portion — trillions worth — are inside us. The bacteria in your mouth, the fungi on your skin, or the viruses in your gut build complex communities that reproduce and adapt quickly.  

We may not be able to see these little critters, but we can feel their effects daily; they serve as good indicators of our health.  

In recent research, Anders Dohlman, PhD, a postdoctoral fellow working in the lab of Matthew Meyerson, MD, PhD, executive director of Dana-Farber’s Center for Cancer Genomics, deployed a genomic tool to detect these microscopic beings and understand how their presence plays a role in cancer.  

“There are microorganisms that are enriched in a tumor compared to surrounding normal tissue, which suggests some kind of selective mechanism on the part of the bug or tumor,” says Dohlman, who published the research in Cell. “We are digging into the ecological interactions of these microbial communities to see what they are doing in a tumor.” 

Getting Buggy  

Tumor-associated microorganisms burrowed in many cancers of the mouth, esophagus, stomach, colon, and rectum can give scientists clues about how cancer progresses. The concept may not be new, but the microbes that scientists are finding associated with certain cancers are just beginning to be understood.  

“When we find a certain type of microorganism in tissues such as the colon, they are either just thriving in a hospitable environment and not causing cancer at all or are promoting the cancer by causing inflammation,” says Meyerson, whose lab uses genomic approaches to understand cancer and develop new treatments.  

In a series of studies, the Meyerson lab pioneered a next generation sequencing method to find pathogens that cause human disease. That approach led to our latest understanding that the overgrowth of Fusobacterium, commonly found in the mouth or gut, can accelerate colorectal cancer in mouse models.  

In this study, Dohlman wanted to take this approach further in more cancers, including the digestive tract, mouth, and throat. However, contamination makes capturing and studying these microorganisms extremely difficult.  

“The amount of microbial signals in these tumors is very small,” Dohlman says. “Just a small amount of contamination throws off results.” 

Dohlman needed a clear method of examining the tumor-associated microbes, so he built one.  

Pathseq-T2T is a computational program that analyzes sampled genetic material to identify microorganisms. This type of metagenomic sequencing provides a greater picture of what is going on in the tumor environment while reducing false positives. The team validated the microbial sequences with synthetic and experimental mixtures of human and microbial DNA. 

The technique was used on more than 16,000 tumor whole genomes — cancer DNA — from the UK 100,000 Genomes Project. This was the largest analysis to date using this technique across roughly 28 cancer types, unlocking a treasure trove of information.  

Unlocking the Treasure Trove  

The team’s first finding was that the number of microbes in cancer is largely limited to cancer types of the mouth, gut, and throat.  

“The cancer microbiome seems to be associated with anatomic sites that are exposed to microorganisms under normal conditions,” Dohlman says. “However, the biodiversity in the mouth, gut, colon and rectum, and esophagus was overwhelming.”  

Many samples were found to have bacteria, fungi, archaea, and viruses. These microbial communities were associated with hypermutated tumors, a pattern that reveals a close relationship between microbial load and tumor mutation across cancer types.  

“Hyper-mutated cancers tended to be colonized at greater levels than non-hyper-mutated subtypes and tended to harbor distinct microbial communities,” Dohlman says. “This seemed to be more related to the mutation burden than the genomic subtype itself.” 

Upon further investigation, the team was hit with a surprise. The parasite Trichomonas was detected in oropharyngeal and colorectal cancers. This was a new discovery for these cancer types.  

“In some cases, Trichomonas can be sexually transmitted and in other cases cause oral infections,” Dohlman says. “While fascinating, further evaluation is needed. What is this parasite doing in these tissues? Is it involved in promoting cancer? Is it a passenger?” 

While this was part of a small subset of tissues, the team was shocked to see it.  

Later, the team revealed a potential relationship between a limited amount of Akkermansia muciniphila — a beneficial gut bacterium — and early onset of colorectal cancer.  

“We noticed almost a tenfold loss of Akkermansia in microsatellite-stable colorectal cancers, which are participles that show how stable DNA is in the cancer, and this is the most common site of some early onset colorectal cancer,” Dohlman says. “Whether this is part of a broader pattern is a question we need to look into.”  

Importantly, the team notes there was no major finding of polyketide synthase-positive Escherichia coli (pks+ E. coli), a bacteria known to produce colibactin, which is linked to early onset colorectal cancer. However, the team’s findings reinforce that early exposure to certain bacteria plays a role in cancer progression.  

Mapping it Out  

Dohlman sees this work as a map of which microbes are present in these tumor tissues. He adds that scientists and clinicians can prioritize specific cancer types by understanding tumor-microbe interactions, which could be relevant in diagnosis and disease management. 

For example, the overgrowth in Fusobacterium, previously discovered in colorectal cancer in the Meyerson lab, was treated in a follow-up study with the antibiotic metronidazole. This treatment reduced the bacteria’s growth and overall tumor progression.  

Meyerson notes that while further evaluation is necessary, unraveling these tumor-associated microorganism interactions can drive the field forward. 

“All these microorganisms are just trying to find a place to live, divide, and replicate, and so they are trying to maximize the replicative potential, and the tumor is trying to do the same thing,” Dohlman says. “There are selective pressures on both communities, and so we may someday be able to leverage this to guide treatment decisions.”

Written by: Maddi Langweil
Medically Reviewed By: Matthew Meyerson, MD, PhD