Science Spotlight

Colorectal cancer cells take bacteria in their luggage when traveling

From the Bullman lab, Human Biology Division

During the last decade, the study of microbiota in cancer has revealed the extraordinary importance of bacteria at every stage of the disease. It is now clear that colorectal cancer biology is tightly associated with micro-organisms. Among them, Fusobacterium nucleatum (Fusobacterium) is of particular interest to Dr. Susan Bullman, who recently joined the Human Biology Division as assistant member after a postdoc at the Dana-Farber Cancer Institute.

Confocal microscopy of co-cultured F. nucleatum and colon cancer cell line HT-29 F. nucleatum red, DNA blue, Actin green.
Confocal microscopy of co-cultured F. nucleatum and colon cancer cell line HT-29 F. nucleatum red, DNA blue, Actin green. Illustration provided by Dr. Bullman.

Abundance of Fusobacterium has been correlated with lower T cell infiltration, advanced disease stage, and poorer survival. However little is known about the mechanism of action operating in the interaction between Fusobacterium and tumor cells. Studies published so far proposed that Fusobacterium could modulate cell adhesion and invasion, or regulate the host immune response. In order to understand the impact of this bacteria on native human colorectal cancer, Bullman and colleagues studied human colorectal cancer samples and published their results in Science.

F. nucleatum invasion of colon cancer cell line HT-29. Red arrows indicate F. nucleatum.
F. nucleatum invasion of colon cancer cell line HT-29. Red arrows indicate F. nucleatum. Illustration provided by Dr. Bullman.

They collected primary colorectal cancer as well as the paired metastatic samples from 101 patients and analyzed the microbiota for each of these samples. For the vast majority of primary tumors infiltrated by Fusobacterium, metastatic sites were also infiltrated with this bacterium. However, none of the metastatic samples associated to primary tumors free of Fusobacterium was infiltrated with the bacterium. This demonstrates that the bacteria colonizes the metastatic sites only when it is present in the primary tumor.

Diagram showing F. nucleatum (red, arrows) infiltrating a primary colorectal cancer and the paired metastatic lesion.
Diagram showing F. nucleatum (red, arrows) infiltrating a primary colorectal cancer and the paired metastatic lesion. Illustration provided by Dr. Bullman.

To assess the role of Fusobacterium on tumor growth, the authors sought to transplant patient-derived xenografts, infiltrated with or free of Fusobacterium, into immunocompromised animals. They first verified that Fusobacterium persisted within infiltrated tumors after several passages into mice. The fact that these bacteria were still present in the tumor after numerous serial transplants supports the hypothesis of a strong dependency between the tumor and its specific microbiota. To assess the potential benefit of therapeutically eliminating Fusobacterium from the tumor, the authors treated both Fusobacterium-free and positive tumors with metronidazole, an antibiotic to which Fusobacterium is sensitive. Remarkably, whereas bacteria-free tumor growth remained unaffected by the treatment, Fusobacterium infiltrated tumors grew slower with antibiotic treatment. This suggests that microbiota modulation may have a role in the treatment of a subset of colorectal cancers, and could change the outcome of this disease. In order to specifically assess the role of Fusobacterium in this antibiotic-mediated effect, the Bullman lab is currently working on new strategies: “Through targeted drug design and small molecule screens we are currently identifying and assessing novel Fusobacterium specific inhibitors,” says Dr. Bullman.

The molecular mechanism underlying this function of support, as well as the modality of colonization of metastatic sites by Fusobacterium are still unclear and Dr. Bullman’s lab intends to address these questions at the Hutch.

This work was supported by the National Institutes of Health.

Fred Hutch/UW Cancer Consortium member Dr. Bullman contributed to this research.

Bullman S, Pedamallu CS, Sicinska E, et al. 2017. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 358(6369):1443–1448. doi:10.1126/science.aal5240

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