Fusobacterium nucleatum: a driver, partner or passenger in colorectal cancer development?

One species in particular has been intricately linked to the disease. Fusobacterium nucleatum is a highly diverse species, commonly found in the tumour microenvironment and stool samples of people with colorectal cancer and is seemingly associated with poorer outcomes.

But what underpins this association? Does its presence trigger tumorigenesis, does it act indirectly, perhaps by modifying the immune response – or is it just a bystander? Answering these questions could open a host of opportunities for prevention, diagnosis and treatment, but has been stymied by the lack of effective models with which to explore them.

A new study from the team taking on our Microbiota challenge and collaborators has begun to fill this niche, with the development of a novel murine model that can be stably colonised by certain F nucleatum strains isolated from people with colorectal cancer. Interestingly, none of these strains were able to trigger cancer development on their own.

We sat down with Dr Jessica Queen (co-first author) and Dr Cindy Sears (corresponding author and Cancer Grand Challenges OPTIMISTICC team co-investigator), both of Johns Hopkins University, to learn more.

Jess: A number of important studies over the past decade have shown that the gut microbiota of colon cancer patients differs from healthy patients. Even within an individual, there are different bacteria in and around tumors compared to healthy parts of the colon. Several of these studies highlighted F nucleatum as a bacterium that flourishes in the tumor microenvironment.

Using mouse models, in vitro assays with a human colon cancer cell line, and whole genome sequencing analysis, we investigated the pro-inflammatory and tumorigenic potential of several F. nucleatum strains isolated from biopsies from people with colon cancer. While these strains differ in their ability to colonize mice and modulate host immune response, none were able to promote colonic tumor formation in mice.

Cindy: F nucleatum is pretty diverse as a species, with at least 4 subspecies and many more strains. I fully believe it contributes to tumor development – but the fact that none of the clinical strains isolated in this study triggered tumorigenesis suggests F nucleatum must be working collaboratively with other bacteria in the gut to drive cancer.

Cindy: It’s been really challenging to develop a mouse model that can be stably colonized by F nucleatum and doesn’t rely on being fed with bacteria every day. Jess and the team’s success in creating a stable colonization mouse model is a major step forward in our ability to investigate how F nucleatum contributes to cancer development. 

Jess: We had 3 main aims with this study:

1. To develop a mouse model of stable F nucleatum colonization
2. To build a library of F nucleatum strains isolated from human colon cancer biopsies
3. To comprehensively compare the 4 different sub-strains that make up this very diverse species

The more we learn about the human microbiome, the more we realize that microbes are important factors in many aspects of health and disease. Our study provides some important steps to addressing important experimental gaps so that we can continue to learn more.

Jess: A multidisciplinary team of investigators each contributed their individual expertise to this project, from bioinformatics to immunology to animal models of disease. This was critical because we wanted to tackle our research questions from multiple angles. We were also able to collect clinical isolates from 3 continents – Europe, Asia and North America – through various collaborations, meaning we were able to test a diverse collection of F nucleatum strains.

There’s a lot of value in the kind of cross-disciplinary work we do in the Sears lab, bringing together people with expertise in microbiology, immunology, gastroenterology, and oncology, and combining forces to tackle important problems in colon cancer. Cancer is certainly a global problem and collaborating with colleagues across boundaries is our best approach to developing the new preventative, diagnostic, and therapeutic tools needed to combat the disease. It’s been really exciting to apply my expertise in microbiology to this field.

Read the article in mBio. 

Jess is a member of Cindy’s lab at Johns Hopkins University. Read Cindy’s feature about how she’s using her background in infectious disease to help advance our understanding of the microbiome’s role in cancer here. 

As told to Emily Farthing.