Researchers at Fred Hutchinson Cancer Center have found that a specific subtype of a bacterium commonly found in the mouth is able to travel to the gut and grow within colorectal cancer (CRC) tumors. The results of their analyses of human tumor tissues, and studies in mice, suggest that this particular lineage, or clade, of Fusobacterium nucleatum animalis (Fna) subspecies, Fna C2, is also a culprit for driving cancer progression, and leads to poorer patient outcomes after cancer treatment.
The findings could help improve therapeutic approaches and early screening methods for colorectal cancer, which is the second most common cause of cancer deaths in adults in the U.S. according to the American Cancer Society. The researchers, led by Fred Hutch cancer microbiome researcher Susan Bullman, PhD, and Fred Hutch molecular microbiologist Christopher D. Johnston, PhD, believe that their study presents significant opportunities for developing microbial cellular therapies that use modified versions of bacterial strains to deliver treatments directly into tumors.
Bullman and Johnston are co-corresponding authors of the team’s published paper in Nature, titled “A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche,” in which they stated, “Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche … this work demonstrates that Fna C2 is a highly virulent subgroup of Fn that should be the primary focus for mechanistic studies and therapeutic drug design in CRC.”
Fn is part of the oral microbiota, and is rarely found in the lower gastrointestinal tract of healthy individuals, but has gained attention as an emerging cancer-associated bacterium, the authors wrote. “Fn species are normal members of the human oral microbiota, and strains from the oral cavity are thought to seed CRC tumors.” Genomic analyses have shown that Fn is enriched in human CRC tumors, relative to non-cancerous colorectal tissues. “High intratumoral Fn loads are associated with recurrence, metastases and poorer patient prognosis,” they further stated. However, there is considerable strain-to-strain variation in Fn genotypic and phenotypic features, and this heterogeneity has made it challenging for scientists to reproduce Fn cancer-inducing phenotypes in animal and cellular models. “… it has been proposed that only a select group of Fn strains may possess carcinogenic capabilities,” the team continued.
For their newly reported study, the investigators, including first author Martha Zepeda-Rivera, PhD, a Washington Research Foundation fellow and staff scientist in the Johnston Lab, wanted to discover how the microbe moves from its typical environment of the mouth to a distant site in the lower gut and how it contributes to cancer growth.
First, they found that the predominant group of Fusobacterium nucleatum in colorectal cancer tumors, thought to be a single subspecies, is actually composed of two distinct lineages, or clades, Fna C1 and Fna C2. “Pangenome analysis revealed that Fna is composed of two distinct clades but only Fna C2 is enriched in the CRC niche,” they wrote. “This discovery was similar to stumbling upon the Rosetta Stone in terms of genetics,” Johnston explained. “We have bacterial strains that are so phylogenetically close that we thought of them as the same thing, but now we see an enormous difference between their relative abundance in tumors versus the oral cavity.”
By separating out the genetic differences between these clades, the researchers found that the tumor-infiltrating Fna C2 type had acquired distinct genetic traits suggesting it could travel from the mouth through the stomach, withstand stomach acid, and then grow in the lower gastrointestinal tract. The analysis revealed 195 genetic differences between the clades.
Then, comparing tumor tissue with healthy tissue from patients with colorectal cancer, the researchers found that only the subtype Fna C2 is significantly enriched in colorectal tumor tissue and is responsible for colorectal cancer growth.
Further molecular analyses of two patient cohorts, including over 200 colorectal tumors, revealed the presence of this Fna C2 lineage in approximately 50 percent of cases. The researchers also found in hundreds of stool samples from people with and without colorectal cancer that Fna C2 levels were consistently higher in colorectal cancer. “Similar to our observation in CRC tumour tissue … our data show that Fna C2 is more prevalent and abundant in the stool of patients with CRC than Fna C1 … and is furthermore the only Fn subgroup significantly enriched in the stool of patients with CRC compared to healthy individuals,” they stated. Interestingly, the team’s experiments showed that in a mouse model of CRC, animals treated using Fna C2 demonstrated an increased number of intestinal adenomas and altered metabolites. “Overall, our results demonstrate the ability of Fna C2, but not Fna C1, to metabolically affect the intestinal milieu towards pro-oncogenic conditions,” they noted.
“We’ve consistently seen that patients with colorectal tumors containing Fusobacterium nucleatum have poor survival and poorer prognosis compared with patients without the microbe,” Bullman commented. “Now we’re finding that a specific subtype of this microbe is responsible for tumor growth. It suggests therapeutics and screening that target this subgroup within the microbiota would help people who are at a higher risk for more aggressive colorectal cancer.” Johnston added, “We have pinpointed the exact bacterial lineage that is associated with colorectal cancer, and that knowledge is critical for developing effective preventive and treatment methods.”
