For a while, scientists thought the trillions of microbes on our bodies lived in landscapes connected to the outside world — our skin, hair, and gut — but research in the last few years has shown that’s not so. When Ravid Straussman, a cancer biologist at the Weizmann Institute of Science in Israel, looked deeper, he and several other research groups around the world found bacteria in the milieu of tumors.

Then, he and other scientists began wondering: if tumors are home to bacteria, then what about another major resident of our microbiome, fungi?  Now, two new papers published in Cell on Thursday, one from Straussman’s lab and collaborators at the University of California San Diego and another from researchers at Weill Cornell Medicine and Duke University, have found genetic footprints of fungi in tumors across the human body.

Together, the studies provide a “nice, rigorous association” between fungi and cancer, said Ami Bhatt, an associate professor of medicine and genetics at Stanford University who did not work on either paper. “It provides pretty compelling evidence there may be rare fungi within tumors,” she said. But the work raises far more questions than it answers. “Are they alive or not? And assuming they really are there, then why are they there? And how did they get there?”

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To find the fungi, Straussman and two of his postdocs, Lian Narunksy-Haziza and Ilana Livyatan, began looking through tumor samples collected in the U.S., Europe, and Israel. “Lian took a hundred-something tumors and began looking for fungal DNA,” Straussman said. “Ilana profiled the fungi across many, many tumor types to study this as much as she could.”

Meanwhile, their collaborators at UCSD searched through the Cancer Genome Atlas database for fungal sequences. The scientists at Duke and Cornell also conducted a similar experiment using the genome atlas. Both groups found what they were looking for.

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“Some tumors had no fungi at all, and some had a huge amount of fungi,” Straussman said. He estimated that some tumors may have 1 fungal cell for every 1,000 to 10,000 cancer cells, based on the amount of fungal DNA the team discovered. Given that even a small tumor may have a billion cancer cells, Straussman said that on the higher end, “it could still be 1 million fungal cells in a tumor, which could have a big effect on cancer biology.”

That may be true, Stanford’s Bhatt said, but she cautioned that the evidence does not suggest cancer tumors are a fungal metropolis. “Finding the fungi is like looking for a needle in a haystack,” she said. “These are very rare sequences, not tumors that are teeming with fungi.”

It does appear that, at the very least, fungal genetics are showing up in tumors, in the cancer cells themselves, and the immune cells that infiltrate the tumor. Why and how they are there is a head scratcher. Maybe, Bhatt offered, because cancer suppresses the immune system, fungi are able to grow there when they might be obliterated elsewhere in the body.

“Or maybe there are immune cells that ate fungi and carried sequences to a tumor site,” she said. “Or maybe since you have a trillion microbes in and on you, it’s just not surprising that every now and then one makes its way into the body.”

But once the fungi are there, if indeed they are alive and doing stuff, then what exactly are they doing? The experiments done thus far don’t probe whether fungi in cancer are merely opportunistic bystanders or if they might be accomplices in cancer. “We don’t have the experiments to present a causal link between tumor initiation or progression and fungi,” she said. “But this really encourages future research to think about designing experiments with microbiome and mycobiome investigations in mind.”

There are morsels of data the teams have uncovered that whet a few hypotheses. It’s possible, Straussman said, that fungi are somehow aiding the tumor to form or grow. “Bits of data here or there showed that fungi correlated with the worst or bad prognosis,” he said. “It’s hard to tell if it’s just a correlation or if the fungi really contributed to the tumor.”

Similarly with bacteria, there may be some interaction between fungi and the immune system that might affect how immune cells combat cancer. “In what we’ve seen in other papers, it always seems to do with the immune system,” Narunksy-Haziza said. That’s also borne out in experiments done on gut bacteria and certain cancer immunotherapies.

Or, since the fungi rarely exist in the body without bacterial neighbors, perhaps there are interactions between fungi, bacteria, and the human body that drive cancer outcomes.  “Fungi can be food for bacteria and vice versa,” Livyatan said. “They can even live within bacteria or bacteria can live within fungi. They can do a lot of biochemistry. Any of those avenues might have an effect.”

Straussman sees those questions as not only fodder for future research, but a way to reframe our understanding of cancer and see it not only as a disease — but also an ecosystem. “As a field, we need to evaluate everything we know about cancer,” he said. “Look at everything through the lens of the microbiome — the bacteria, the fungi, the tumors, even viruses. There are all these creatures in the tumor, and they must have some effect.”

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