Have you ever amazed your friends and relatives with the fact that, when you tally up the microbes living inside and on your bodies, they match or even outnumber your own cells? Well, it turns out that human cancers are no exception; tumors can host an enormous assortment of microbial life. While ongoing research into this so-called ‘tumor microbiome’ is still in its infancy, the field is beginning to paint a complex picture of interactions between host tumor cells and their resident bugs—interactions which span the range of mutually beneficial to potentially disease-regulating. The Bullman Lab in the Human Biology Division at the Fred Hutchinson Cancer Center studies the tumor microbiome to inform cancer treatment. The group recently published a paper in Cell Reports detailing one striking story relevant to this mission.
This recent study builds on a previous finding from the Bullman Lab and others: namely, that the bacterium Fusobacterium nucleatum (Fn), a species commonly found in both normal and cancerous gastrointestinal tissue, may have active roles in enhancing tumorigenesis and cancer growth. While a concerned observer might confront these findings and conclude that we should be treating colorectal cancer patients with broad-spectrum antibiotics, Dr. Bullman is quick to point out the limitations of this approach. “The challenge with broad-spectrum antimicrobials is that they will knock out a range of microbes, including beneficial gut microbiota, which may make patients more susceptible to nosocomial (hospital-acquired) infections. Additionally, tumor microbial diversity appears to be beneficial in some cases by enhancing responses to therapies and priming the host immune system—another reason broad-spectrum antibiotics may not be the best approach here.” Thus was born a scientific quest—led by post-doctoral researcher Kaitlyn LaCourse—for a more precise weapon: an antimicrobial compound which would specifically target tumor-resident Fn.
To identify specific inhibitors of Fn growth, the team screened a library of nearly 2,000 chemical compounds against an Fn strain isolated from a colorectal cancer sample. While the screen returned 34 drugs which inhibited Fn growth compared to control conditions, Dr. LaCourse and colleagues were surprised to find that a significant proportion of these 34 compounds were so-called ‘antineoplastic agents’—cancer drugs. Among these drugs was 5-fluorouracil (5-FU), a mainstay chemotherapeutic used to treat colorectal cancer which is thought to work by inhibiting cancer cells’ ability to replicate their DNA. Surprised by these initial results, the researchers decided to expand on this finding and showed that Fn cultures isolated from diverse tissue sources were indeed sensitive to 5-FU at concentrations relevant in a cancer treatment setting.
While the notion of an anti-cancer drug inhibiting the growth of a cancer-promoting microbe is already thought-provoking, in order to validate 5-FU as a specific agent against Fn, the researchers investigated whether 5-FU also inhibited the growth of other colorectal cancer-associated bacterial species. To their surprise, none of the four other bacterial species they tested showed sensitivity to 5-FU, prompting them to investigate whether these species were able to somehow detoxify 5-FU and thereby avoid its inhibitory effects. Indeed, one of the strains, an E. coli subspecies, was able to actively metabolize 5-FU into a nontoxic byproduct. Realizing that these different bacterial species—including Fn and E. coli—often coexist in colorectal tumors, the researchers posed a final, juicy question: could it be the case that tumor-resident E. coli protected both Fn and host tumor cells from the inhibitory effects of 5-FU by metabolizing it to a nontoxic product? Through a series of in vitro tumor cell assays and metagenomic experiments in ex vivo patient-derived tumor models, they were able to answer this question with a definitive ‘yes.’
Thus—as is all too often the case in science—reality is more complex than we thought, and there is always more work to do. Studies like this one from the Bullman Lab highlight the importance of understanding some of the not-so-human aspects of human biology which influence not only the diseases we suffer from, but their treatment as well. As Dr. Bullman notes, “Our findings demonstrate a potential interplay between cancer-treating drugs and a patient’s unique microbiota. We believe that this variable should be considered when deciding on optimal treatment approaches, and we hope that our work will give us a better understanding crucial to accomplishing that goal.”
The spotlighted research was funded by the Seattle Translational Tumor Research program, the Washington Research Foundation, and the National Institutes of Health.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Susan Bullman contributed to this study.
LaCourse, K. D., Zepeda-Rivera, M., Kempchinsky, A. G., Baryiames, A., Minot, S. S., Johnston, C. D., & Bullman, S. 2022. The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota. Cell Reports. 41(7), 111625.