Composite and images of Drs. Johnston and Bullman by Robert Hood/Fred Hutch News Service; Image of Dr. Angela Ting courtesy of the Cleveland Clinic
Our microbiomes, the communities of microbes living in and on our bodies, influence everything from our weight to our cancer risk. But many of the mechanisms that link bacteria to our health remain murky. Now, a multidisciplinary team of scientists at Fred Hutchinson Cancer Research Center and the Cleveland Clinic’s Lerner Research Institute plan to study a new way they suspect some bacteria may be able to cause cancer by modifying human DNA.
The team is supported by a $1 million, three-year award from the W.M. Keck Foundation, one of the nation’s largest philanthropic organizations. With this funding, they’ll test whether bacterial systems that have evolved to defend against viral infection may also be able to change how our own genes are turned on or off, and whether these changes could promote cancer.
“The goal is to look for evidence of very specific bacteria-associated changes in human cancer DNA,” said project co-lead Dr. Angela Ting, an investigator at Cleveland Clinic’s Lerner Research Institute. She studies how molecular modifications to DNA, which regulate which genes are switched on and off — broadly termed epigenetics — change in cancer.
She has teamed up with Dr. Christopher D. Johnston, a Hutch synthetic microbiologist who studies the epigenetics of bacteria within the human microbiome, and Hutch cancer microbiome expert Dr. Susan Bullman, to examine their tantalizing, but as-yet-untested, hypothesis. If it proves true, the scientists will have revealed an entirely new way that bacteria could directly alter human DNA, and perhaps even cause disease. A better understanding of how cancer develops or progresses can help researchers create better cancer prevention strategies, better diagnostics and more-tailored treatments for individual patients’ tumors.
The idea that bacteria can promote cancer isn’t new — Helicobacter pylori, for example, is a well-known risk factor for stomach cancer. H. pylori is thought to cause cancer by triggering chronic inflammation that, in turn, damages our DNA. Johnston, Bullman and Ting suspect a different mechanism, in which bacteria may directly alter or damage DNA and change the genes that are turned on and off in otherwise normal cells.
Mutations that change the letters of our DNA code can have big effects on whether a gene is turned on, turned off, loses an important tumor-suppressing function, or gains a new tumor-promoting function. Our cells can also use epigenetic changes, which don’t alter DNA sequence, to control whether genes are turned on and off. Small epigenetic molecules called methyl groups are a class of DNA modification that, in humans, generally help turn genes off when they attach to the DNA strand.
“DNA methylation is one of the key global epigenetic changes that we see throughout cancer,” Ting said. “There have been countless examples of how abnormal methylation can very effectively turn off tumor-suppressor genes, which then promotes cancer development and cancer growth.”
But it’s usually unclear how these methylation changes begin.
“There’s a lot of speculation, but not a lot of actually concrete studies that pinpoint how those changes occur,” Ting said. “It’s one of the biggest questions in the field of medicine, and one our specific project hopes to address.”
Ting, Johnston and Bullman propose that these cancer-causing methylation changes may arise from bacterial interference. They suspect that certain bacteria can damage our cells’ DNA, including by changing their epigenetics and shutting down genes that usually prevent tumor formation.
Johnston’s lab focuses on the bacterial defense systems that the team theorizes could be meddling with our cells’ DNA. They are enzymes whose activity is influenced by the presence or absence of methyl groups on DNA with a specific target sequence.
Though these systems have evolved to protect bacteria against DNA from invading viruses, they can modify DNA — by cutting or adding epigenetic molecules — from any non-bacterial species with the right sequence, including humans. (Many decades before CRISPR, scientists co-opted such systems’ DNA-cutting capabilities to understand how genes worked by cutting and pasting different DNA sequences.)
One of the bacterial species known to produce these types of systems is Fusobacterium nucleatum, which is often enriched in the microbiome, or microbiota, of colorectal tumors.
“Recent studies suggest that most solid tumors harbor an intra-tumoral microbiota, and each solid tumor type has a distinct intra-tumoral microbiota,” Bullman said.
Bullman has shown that F. nucleatum can enter human cells, and, once inside, move toward the nucleus, the membrane-wrapped space where cells store their DNA. She also found that tumors with Fusobacteria in their microbiomes have patterns of gene activation suggestive of altered methylation.
Could the bacteria be the cause?
“Bacteria methyl-modify their DNA in subtly different ways than human cells do, so it’s possible that there is a hidden layer of information within human cancer DNA,” Johnston said.
The team suspects that bacteria could be altering human DNA, by cutting it or adding their own array of methyl groups. Could these modifications change which genes are turned off?
“If this is occurring, and you were not looking for the very specific telltale signs of bacterial modifications, then you could easily miss them,” he said.
The team knows it's going out on a limb. Government granting agencies like the National Institutes of Health prefer projects to remain closer to the ground, scientifically speaking, but support from the W.M. Keck Foundation will get the project launched.
“When we got the funding, I stepped into the lab and said, ‘We finally have the money to turn science fiction into science reality!’” Ting recalled.
The team aims to test their hypothesis that bacteria can modify our cells’ epigenetics with F. nucleatum in the context of colorectal cancer. The first step will be to develop the necessary tools and methodologies they’ll need to explore this new field.
If their hypothesis pans out, the findings could be paradigm-shifting in all three scientists’ areas of study, they said.
“It’s rare that three scientists from very disparate fields get to collaborate so meaningfully and deeply. When that happens, it’s very exciting,” Johnston said.
About the W. M. Keck Foundation
The W. M. Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation’s largest philanthropic organizations, the W. M. Keck Foundation supports outstanding science, engineering and medical research. The Foundation also supports undergraduate education and maintains a program within Southern California to support arts and culture, education, health and community service projects.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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