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Can a tumor that acts like a microbe help us develop better cancer therapies?

Understanding the genetics underlying spontaneous regression of an infectious tumor in Tasmanian devils could point us toward new treatment targets
photo of a Tasmanian devil at night
Rare contagious tumors — called devil facial tumor disease — have brought Tasmanian devils to the brink of extinction, but new research could shed light on its weaknesses and point us toward new treatment targets for a variety of cancers. Photo by Heath Holden

A tumor that jumps from host to host. A tumor that evolves to slow itself down. Both defy expectations — and both are the same tumor. Rare contagious tumors have brought Tasmanian devils to the brink of extinction, but new work from scientists at Washington State University and Fred Hutchinson Cancer Research Center could shed light on its weaknesses.

The study, published last month in the journal Genetics, showed that a single mutation underlies some cases of spontaneous regression — meaning the cancer is disappearing on its own — of devil facial tumor disease, or DFTD. Surprisingly, the mutation doesn’t change gene function: Instead, it turns on a gene that slows cell growth, at least in the lab.

Though the findings have most immediate relevance for scientists working on Tasmanian devil conservation, they could someday translate to human health. Current cancer therapies focus on removing every trace of the tumor, often through toxic or debilitating treatments, said Dr. David Hockenbery, a cancer biologist at Fred Hutch who contributed to the study.

“If there were ways that tumors could be tricked into regressing without having to administer cytotoxic drugs or deforming surgeries, it would be a major advance,” he said.

A tumor that jumps around

We’re familiar with infections that cause cancer: HPV causes cervical cancer and Helicobacter pylori, gastric cancer. The Hutch has even dedicated a research group, the Pathogen-Associated Malignancies Integrated Research Center, to studying cancers caused, directly or indirectly, by infection.

But just occasionally, the cancer is the infection.

Such is the case with a contagious cancer in Tasmanian devils, carnivorous marsupials whose habitat has shrunk to the island state of Tasmania off the southeastern coast of Australia. Since the mid-1990s, a deadly facial tumor, spread between devils by biting, has decimated the natural population of devils. Surprisingly, lightning struck twice: A second infectious facial tumor, DFT2, was first observed in 2014.

photo portrait of David Hockenbery
Dr. David Hockenbery is a cancer biologist at Fred Hutch. Photo by Robert Hood / Fred Hutch News Service

“The tumor cells basically take up residence in the new host, like a tissue graft,” Hockenbery said. “And for the two tumors, each animal that has that tumor, has the exact same tumor.” Each clump of tumor cells is a direct descendant of the original tumor.

Truly infectious tumors are rare. Besides the devil tumors, there are just a few other known examples, including a sarcoma in Syrian hamsters spread via a mosquito intermediate and a contagious venereal cancer in dogs. Scientists have also found transmissible cancers in certain species of cockles, mussels and clams (including one that jumped species). There are no naturally contagious tumors in people, though doctors do ensure that transplants don’t harbor hidden tumors in the transplanted tissue.

The dog tumor may be the longest living tissue on the planet: It’s a living remnant of a dog that lived about 11,000 years ago in Asia. Like the dog tumor, the devil tumor is essentially a chunk of one animal that’s gone on to take root and thrive in thousands of other animals. But unlike the dog tumor, which usually regresses somewhat and doesn’t kill the affected dog, DFTD is almost always deadly.

Because these unusual tumors strike an iconic species, DFTD and DFT2 are the subject of much study. Scientists hope to gain insights that improve conservation efforts for Tasmanian devils as well as understand tumor evolution and the co-evolution of a pathogen and its host.

One of the scientists studying co-evolution — or how two entities, in this case devils and their tumors, evolve in concert with each other — is Dr. Mark Margres, now a postdoctoral fellow at Harvard University in the laboratory of Dr. Michael Desai. Margres, who led the study while a postdoc in the WSU lab of Dr. Andrew Storfer, will soon become an assistant professor at the University of South Florida. He also studies co-evolution between rattlesnakes and their prey.

Though ferocious with each other, Tasmanian devils take mild handling by people quite tamely, making it easy for investigators to humanely capture devils, collect tissue samples and tag the animals for monitoring before releasing them back into the wild.

As researchers work to save the devils, the animals’ tumors give them an unprecedented opportunity to watch tumors naturally evolve: no drugs, no surgery. And sometimes, they regress. Perhaps, said Storfer, the studies could help scientists gain insights that are relevant to human cancer.

“Can we learn anything that could be applied to understanding and possibly treating cancer in the future?” he said.

Dr. Rodrigo Hamede of the University of Tasmania gently releases a Tasmanian devil after it was studied by cancer researchers because of the rare contagious tumors that have brought the species the brink of extinction. Scientists hope to learn why mutations are causing some tumors to disappear, to help the Tasmanian devils and potentially human health in the future. Video courtesy of Dr. David Hockenbery

A regulatory mutation underlies tumor regression

Margres and Storfer had previously examined devils themselves for genetic markers associated with tumor regression. Margres’ next step was to examine the tumors’ genetics. He screened eight regressed and seven non-regressed DFTD and DFT2 tumors for genetic differences, starting with a list of genes already known to be associated with cancer.

“When we started looking at that list, we weren't really finding very much at all,” Margres said.

So Margres widened his net. One gene that jumped out was RASL11A, a little-studied member of a family of genes heavily implicated in human cancer. All seven tumors had a mutation in RASL11A, and six of the seven had the same mutation: a single-letter difference in the gene’s DNA alphabet. Surprisingly, the mutation wasn’t one that would alter the RASL11A protein’s function. Instead, the mutation was what’s known as a “regulatory” mutation, one that changes whether a gene is turned on or off.

Margres and the team found that RASL11A was turned off in tumors that had not regressed but was turned on in regressed tumors that shared the regulatory mutation.

He and Storfer turned to cancer expert Hockenbery and his Hutch colleague and CRISPR expert Dr. Patrick Paddison to help test whether the RASL11A regulatory mutation had functional consequences for devil tumor cells. Tools like CRISPR, the precise gene-editing method that’s swept science in recent years, have made it possible to do unprecedented genetic work on animals, like Tasmanian devils, that can’t be studied in labs, Hockenbery said.

Using genetic tools to turn RASL11A on in DFTD and DFT2 cells, the Hutch team found that those with the mutation grew significantly slower in lab dishes compared to devil tumor cells without the mutation. (In contrast, the RASL11A mutation enhanced the growth of normal devil skin cells.)

The results point to unexpected tumor-cell dynamics, Hockenbery said. It’s difficult to imagine how slower growing cells could overtake faster-growing competitors, he said: “You really have to stretch your imagination.”

Because devil facial tumors are infectious, Hockenbery speculated, their evolution may be shaped by the need to transmit to a new host. A slower-growing tumor that leaves its host alive longer may be able to spread to more animals and ultimately win out over a fast-growing but deadlier variant.

It may also be evidence of the mutual adaptation that devils and their tumors are undergoing, said Margres. He’s seen something similar in his rattlesnake work.

“Regulatory mutations … actually seem to underlie adaptation in rattlesnakes much more frequently than mutations that change the function of the protein through its amino acid sequence,” he said.

photo portrait of Dr. Mark Margres
Dr. Mark Margres led the study during his postdoctoral research at Washington State University. Photo courtesy of Dr. Mark Margres

Developing a lab model for devil tumors

Whether the need to transmit explains how a growth-slowing mutation was able to take hold in contagious devil tumors remains to be determined. The findings have also raised other questions, such as whether the tumors that share a RASL11A mutation are all derived from the same original tumor, or whether the mutation arose several times in separate tumors.

Though it’s less studied than other Ras family members, other work has shown that RASL11A is also turned off in some prostate and colon tumors, suggesting it normally suppresses tumor formation. The team is working to learn more about how this may work. One current hypothesis is that it’s linked to RASL11A’s role in creating the molecular machines that make proteins, a process that often changes in tumor cells.

One of the biggest challenges faced by researchers studying wild animals is the lack of easily manipulated disease models. Tasmanian devil tumors can’t be successfully transplanted into mice with functional immune systems. One of the ways that tumors are thought to be able to jump from devil to devil is by evading the devils’ immune systems, so Hockenbery and his colleagues are working to develop “devilized” mice, or mice that have Tasmanian devil immune systems that would make it possible to transplant tumors and study how they grow (and fly under the immune system’s radar) in an animal instead of Petri dishes.

Margres said the team is also looking at the effects of other promising mutations in regressed tumors.

“I think it's much easier to design therapeutics and treatments around a simple genetic basis,” he said. “If you need to target thousands of genes in your therapy, then that that becomes much more complicated. Whereas if you can identify these large-effect genes, potentially they can have very large effects on tumor growth,” he said.

Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. 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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Last Modified, August 26, 2020