40 THE SCIENTIST | the-scientist.com
ADAPTED FROMSCIENCE, 371:EABC4552, 2021.; ILLUSTRATION BY © NICOLLE FULLER, SAYO STUDIO“But then I got curious.”
In subsequent experiments, Straussman confirmed that it
was the bacteria that were rescuing the cancer cells from chemo-
therapy: when he treated the fibroblasts with an antibiotic, they
no longer protected cancer cells from gemcitabine, and when
he infected other stromal cells with Mycoplasma, it endowed
them with the ability to shield cancer cells from the drug. “So
we know for a fact it wasn’t the stromal cells that rescued the
cancer cells from chemotherapy, but actually it was the Myco-
plasma that did that.”
The question remained whether such bacteria are naturally
present in cancer. Contrary to the common dogma at the time
that tumors were sterile, Straussman says he wondered if the
cancerous growths could in fact be hosting microbial life, like so
many tissues in the human body that modern genomic tools had
revealed to harbor their own microbiomes. Gemcitabine was then
a first-line treatment for pancreatic cancer, and is still commonly
used. “If there are bacteria in pancreatic cancer and bacteria do
such a beautiful trick, this can be really interesting.”
When Straussman accepted a faculty position at the Weizmann
Institute of Science in Israel in 2013, he decided to pursue this line
of research. Along with Weizmann colleagues and collaborators
back at the Broad, Straussman sequenced samples from 113 human
pancreatic cancers and scoured the results for bacterial DNA. Sure
enough, the researchers found genetic signatures of bacteria in 76
percent of them. “We never found Mycoplasma in pancreatic can-
cer, but we found many other bacteria,” says Straussman, “and we
found that [when] we isolated these bacteria from tumors, they can
also rescue cancer cells from chemotherapy” in vitro.The next piece of the puzzle, then, was how. Further research
showed that bacteria lived inside the cancer cells near the nuclear
envelope. There, they would take up gemcitabine before it could
reach the cell’s genome and they’d cleave an amine group from
the drug, effectively deactivating it. The findings were so unex-
pected that it took one of the group’s own technicians more than
a year to be convinced of their validity, notes Straussman, who has
since filed for a few patents related to the presence of bacteria in
tumors. When the team published its work in Science in Septem-
ber 2017, it was one of the first conclusive demonstrations that a
tumor outside the gut had bacteria living within it.^2
While the thinking at the time was that cancers were gener-
ally germ-free tissues, there had long been reports of microbesin tumors. The problem was that contamination could not be
ruled out in most cases. But in the less than five years since
Straussman and his team revealed those findings, the evidence
for the idea has exploded as various groups have carefully docu-
mented the presence of cancer type–specific microbial commu-
nities. There have been “literally dozens of other papers,” says
microbiome researcher Rob Knight of the University of Cali-
fornia, San Diego (UCSD), and these have provided “plenty of
evidence that tumors do have their own microbiome.” Indeed,
this January, Douglas Hanahan of the Swiss Federal Institute
of Technology Lausanne added “polymorphic microbiomes” to
the famous list of cancer hallmarks, noting that “while the gut
microbiome has been the pioneer of this new frontier, multiple
tissues and organs have associated microbiomes.”
Researchers are moving quickly to turn these discoveries
into clinically useful tools. The mere presence of microbes in
tumors could provide a conceptual basis for new cancer diag-
nostics, and Knight recently cofounded Micronoma, a company
that aims to develop such tests based on bacterial nucleic acid
signatures in the blood. Researchers are also exploring the pos-
sibility of manipulating the tumor microbiome to treat cancer,
and Straussman says he is now in the process of launching a new
company, Baccine, to do just that. (He also consults for Biomica,
which is focused on gut microbiome–based therapeutics for a
range of diseases, including cancer.)
But while some scientists are already looking toward poten-
tial clinical applications, many basics of tumor microbiome biol-
ogy remain unresolved. Some of the most pressing questions
pertain to whether and how microbes are influencing the devel-
opment and progression of cancer, as well as patients’ responses
to therapy. “There is a lot of fundamental biology that is yet to
be discovered,” says Micronoma cofounder and executive Greg
Sepich-Poore, a recent PhD graduate from Knight’s group.
“Describing the presence of these bacteria and viruses, it’s
only step one,” agrees virologist Nadim Ajami, director of sci-
entific research for MD Anderson’s Program for Innovative
Microbiome and Translational Research (PRIME TR), an
effort focused on interrogating microbe-host interactions in
cancer. “What we’re really after is [understanding] their role
[in the] onset of cancer, progression of disease, response to
therapy, with an eye on how can we use all that information to
perhaps prevent the development of cancer or increase ther-
apy efficacy.”Tumors are melting pots
The overturning of the tumors-are-sterile dogma is thanks in
large part to the development of next-gen sequencing and the
curation of massive data sets of cancer genomes. As MD Ander-
son’s Jennifer Wargo explains, “Whenever you do whole-genome
sequencing, not only do you get human reads, you also get micro-
bial reads.... Rather than [filtering] microbes out, we can actu-
ally get a lot of clarity about what microbes are there [and] what
function do they have.”Everything that has to do with tumor biology can
now be reexamined. There's endless directions
in which we can go.
—Ravid Straussman, Weizmann Institute of Science