The study of the relationship between the intestinal microbiome and cancer received a powerful push in 2019 with the awarding of a $25 million Grand Challenge grant from Cancer Research UK, a charity based in the United Kingdom, to an international team
of 14 scientists. The program's focus is explicit in its name: Opportunity to Investigate the Microbiome's Impact on Science and Treatment In Colorectal Cancer, or OPTIMISTICC. Its goal is ambitious:
to pinpoint how the microbiome impacts the onset and development of colorectal cancer and to use those findings to improve outcomes for people with the disease. Its leaders are Garrett and Matthew Meyerson, MD, PhD,
director of Dana-Farber's Center for Cancer Genomics.
The program brings together the elements — data, tissue samples, and scientific talent — needed for a sustained assault on the question of whether the microbiome impacts cancer and, if it does, how that relationship can be manipulated to help patients.
"We have computational biologists, cancer genomicists, clinical trial leaders in colon cancer, epidemiologists, immunologists, and microbiologists on a dream team that can focus like a laser on colon cancer and the microbiome," Garrett says. "It's a thrilling
and transformative opportunity for microbiome science and for our patients."
The program's clinical flagship study, known as MICROCOSM (for MICRObiome of Colorectal Cancer: Longitudinal Study of Mechanism), is collecting long-term health information and tissue and stool samples from more than 2,500 people across North America
and Europe who were being treated for colorectal cancer. Researchers are not only exploring whether the microbiome plays a role in the formation or growth of colorectal cancer but also whether it has an impact, positively or negatively, on the effectiveness
of treatment and the side effects of various therapies.
"With MICROCOSM, we established an infrastructure to collect these samples and generate data from them — on the genetic makeup of the tumor cells and bacteria cells, on the type of immune system cells mixed in with them — and really begin to crack whether
there's a link between the microbes that live in a person's gut, in their tumor, and their response to treatment," says Kimmie Ng, MD, MPH, co-director of the Colon and Rectal Cancer Center and director of the Young-Onset Colorectal Cancer Center at Dana-Farber, as well as a member of the OPTIMISTICC team that is co-leading MICROCOSM. "And layered on top of that, we'll have data on
everything from where participants live to what they eat to how much they exercise, which will help us answer a wide range of questions about how environmental factors shape the microbiome and influence treatment response."
New Tools to Identify Intestinal Microbes
Though scientists have speculated about a link between the microbiome and colon cancer for ages, it is only relatively recently that technology has handed them the tools needed to obtain a definitive answer. A key advance was Meyerson's development in
the early 2000s of a method called sequence-based computational subtraction. Though its name is a mouthful, the concept is simple: collect a stool sample from an individual, sequence the DNA of all the cells within it, and subtract out the human DNA.
What's left is the DNA of intestinal microbes — bacteria, viruses, fungi, and parasites.
The approach was powerful in principle, but the DNA-sequencing technology of the time didn't have the capacity to process large-enough numbers of cells. About a decade later, Aleksandar Kostic, a PhD student in Meyerson's lab (and now a researcher at
Joslin Diabetes Center), created a more powerful system, called PathSeq, that uses next-generation sequencing. With it, he analyzed colon cancer samples to see what types of bacteria were present.
In a study published in 2011, Meyerson, Garrett, Kostic, and colleagues at Dana-Farber and the Broad Institute of MIT and Harvard reported that they'd found strikingly high levels of the bacterium Fusobacterium nucleatum in colorectal cancers.
What made the discovery particularly notable was that Fusobacterium is usually found in the mouth, not the bowel.
The study was followed by another, by Meyerson, Garrett, and Marios Giannakis, MD, PhD, of Dana-Farber, and Shuji Ogino, MD, PhD, now at Brigham and Women's Hospital,
that indicated that patients whose colorectal tumors harbored high levels of Fusobacterium had worse prognoses than those whose tumors had lower levels of the bug. A 2017 study led by Meyerson and co-authored by Ng and Giannakis found that
when colorectal cancer cells metastasize to other parts of the body, the roving cells brought along some of their bacterial cronies from the colon, including Fusobacterium nucleatum, like mementos from home. In studies with animal models
carrying the metastatic cells, the researchers found that treating the animals with an antibiotic that targets many bacteria, including Fusobacterium, caused tumor cell proliferation to decline.
Findings like these point to an association between certain gut bacteria and tumors of the colon. But as scientists are quick to point out, association is not causation. As Meyerson puts it, "What we don't know yet is do these bacteria actually provoke
the growth of the cancer or are they merely opportunistic: are they there primarily because the cancer provides a good environment for them? Or is it some combination of the two? Despite a lot of research in the field, we really don't have a clear
answer to that question."