Focus Feature: Researchers collect critters to unlock cancer secrets

Classical model systems such as cell culture and mice are key to understanding cancer. But what can we learn by examining how cancer works in other models? Animals like naked mole rats and Tasmanian devils offer a new perspective on how cancer works and how we can treat it.

Jun 01, 2021
Natalya Ortolano, PhD
Focus Feature: Researchers collect critters to unlock cancer secrets

Your knowledge of  Tasmanian devils, naked mole rats, whales, and squirrels may be limited to what you’ve seen on Cartoon Network or the Dis­covery Channel, but some researchers con­sider these critters an untapped resource for cancer research. 

Researchers started asking questions about cancer in the 1700s. Classical models like mice, rats, and cell culture provided foundational insights on cancer mechanisms and even led to effective treatments such as chemotherapy. However, there is still no true “cure.” 

Some creative scientists think that we’ve simply been looking in the wrong places. 

“Just because mice were used by biologists for a very long time and there are all kinds of tools available doesn’t mean they are the best place to look,” said Vera Gorbunova, Doris Johns Cherry professor of biology and medi­cine and the co-director of the aging research center at the University of Rochester, who pri­marily studies cancer in naked mole rats. 

Some researchers think that we should focus on animals that are better at fighting cancer than we are, like naked mole rats and blue whales. Others think that getting out of the lab and studying cancer in the wild for­ests of Tasmania is the way to go. Some think that we don’t even need to get out of the house; finding a way to treat cancer in dogs may be the solution. 

All of these models share one thing: they challenge our preconceived notions about how cancer develops. Dogma-challenging researchers who work with these animal models think that a change in perspective may be just what we need to develop better treatments, and possibly even find the ever-elusive cancer cure. 


Are naked mole rats the fountain of youth? 

Gorbunova was destined to be a scientist — both of her parents were physicists. She was cap­tivated by research and its ability to answer seemingly unanswerable questions. Since she preferred animals to quantum mechanics, she pursued an undergraduate degree in biology. 

During her sophomore year, Gorbunova attended a guest lecture where she learned about how cells age, and she was hooked. Her fascination with aging grew when she realized that it was our century’s deadliest disease. 

Infectious diseases like the bubonic plague aren’t wiping out vast swaths of the population anymore. People live longer than ever. Last year, heart disease and cancer were the leading causes of death (1). Although viral pandemics are making a comeback, even COVID-19 dis­proportionately affects the elderly, often due to aging related pre-existing conditions. 

By slowing down the aging process, Gorbu­nova hopes to “treat” all aging related diseases and even, in theory, protect the aging popula­tion from severe COVID-19 infection. 

“If we can find a way to prevent the bio­logical processes that lead people to become susceptible to these diseases, that may be a lot easier [than treating them],” said Gorbunova. 

Gorbunova thinks that the answer may lie in a hairless, buck-toothed rodent called the naked mole rat. 

Naked mole rats live longer than any other rodents. They can live nearly thirty-five years — a mouse the same size only lives four. While mice are more susceptible to cancer than humans (2), naked mole rats have an incredibly low incidence of cancer, and they don’t experience age-related disease at all. 

Naked mole rat’s eternal youth attracted Gorbunova like a moth to the flame. If she could find the rat’s secret, she may not find a “cure” for cancer, but she may be able to prevent it from developing in the first place. 

“I am interested in mechanisms that nat­urally evolved to provide resistance to can­cer and other diseases,” said Gorbunova. “Obviously, we have to study animals that live long and don’t develop these diseases in the first years of life.” 

Gorbunova’s graduate student Christo­pher Hine, now an assistant professor at the Cleveland Clinic, found the first can­cer prevention mechanism in naked mole rats: early contact inhibition (3). Usually, cells stop growing once they touch each other to prevent unregulated proliferation and tumor formation. Naked mole rat cells stop growing in culture even before they fully contact one another, unlike somatic mouse and human cells. Cancer cells aren’t limited by contact inhibition, so Gorbu­nova found it obvious that early contact inhibition served as a cancer prevention mechanism in naked mole rats. 

The question remained: how did the cells know to stop proliferating so much earlier than other cells? 

The first clue was an unusual, viscous substance in the media of the naked mole rat cell cultures. Most researchers see turbid media and think that their cell cul­ture is contaminated, but that didn’t add up. Only the naked mole rat cultures had cloudy media, and ablation of early con­tact inhibition in the cultures removed the viscous substance. 

Like many research stories though, the story we tell is often the truth packaged with a nicely tied bow. 

“Many people noticed [the media] because it would clog the vacuum lines in the tissue culture room. So, we noticed this, and we didn’t know what it was, so we thought, ‘Chris needs a PhD project, so why don’t we find out?’” said Gorbunova, chuckling. “We didn’t know where to start.”

Hine first compared the proteins in media from naked mole rat cells and mouse cells on a protein gel to see if there were any dif­ferences. Naturally, he didn’t see any. 

So he did what every good researcher does when they aren’t sure what to do next: he googled it. YouTube came through with a documentary about a carbohydrate known as hyaluronan that Hine thought might be the vacuum clogging culprit.

Hyaluronan is a clear, gooey substance secreted by cells to become part of the extra­cellular matrix. It regulates many cellular processes, including cell-to-cell interac­tions and proliferation.

Hine discovered that naked mole rat fibroblasts produced high levels of a version of hyaluronic acid that is five times larger than that found in mice or humans. This so-called high molecular mass hyaluronic acid seems to tell fibroblasts that cells are begin­ning to come in contact with each other before the cells become too dense in culture.

Gorbunova’s group postulated that high molecular mass hyaluronic acid may be overly abundant in naked mole rat skin to keep it flexible while the rats tunnel in the ground. Cancer prevention was probably just a bonus.

Gorbunova now searches for drugs to enrich the amount of high-molecular mass hyaluronic acid in humans to prevent regrowth of cancer or its development in patients with high risk.

Hyaluronic acid is just one of the unique anti-aging mechanisms Gorbunova and her team discovered. They recently identified novel mechanisms for regulating telomere length and DNA methylation to prevent cel­lular senescence and DNA damage.

As much as Gorbunova loves her naked mole rats, they don’t love her back.

“Maybe the most disappointing part is that they pay no attention to you,” said Gor­bunova. “They live in colonies and have quite busy social lives.”

Although unrequited love isn’t her main motivation, Gorbunova also investigates other animals to determine how they avoid getting cancer.

Gorbunova is working out cancer pre­venting processes in long-lived, cancer resis­tant animals such as blue whales and grey squirrels, with the goal of moving their can­cer resistance mechanisms into the clinic.

“I want to understand how these mecha­nisms work from the genetic point of view, and then the next step is to develop small molecules and pharmaceuticals that can swing the system in the same way as a grey squirrel or a naked mole rat,” said Gorbunova.


Bigger isn’t always better — unless you’re a whale

Daniela Martinez, a post-doctoral research­er in the department of biochemistry and molecular biology at Thomas Jefferson Uni­versity, also wants to understand how cer­tain mammals stave off cancer. Naked mole rats are on her agenda, but right now she’s using comparative genomics to understand how tumor suppressor genes were positively selected during the evolution of whales.

Martinez didn’t see many whales in her landlocked hometown of Bogotá, Columbia, but the river dolphins in the Amazon nearby fascinated her. As an evolutionary biologist, she still doesn’t see many whales, but she spends a lot of time analyzing their genomes.

Daniela Martinez, a post-doctoral researcher in the department of biochemistry and molecular biology at Thomas Jefferson University, uses comparative biology to understand cancer resistance in cetaceans.

She first married her love for large, water-roaming cetaceans such as whales and dol­phins with her enthusiasm for research as a graduate student at the Austral University of Chile. She needed an open scientific ques­tion, and how cetaceans, the largest animals to roam the planet, manage to evade cancer, was certainly a mystery.

Cancer is the burden of being a multicel­lular organism. The more cells you have, the more likely they are to be damaged by environmental stresses and aging. Dam­age often causes mutations, which lead to uncontrolled proliferation or cell death, ultimately causing cancer.

However, some whales have one thou­sand times more cells than humans and can live over a hundred years, but their cancer rates are low. This disconnect is called Peto’s paradox.

“The paradox is the observation that can­cer should increase with the number of cells [in an organism] because random errors in the DNA accumulate with increasing cell divisions and increasing longevity,” said Martinez. “Long-lived species or big species should have more risk of cancer than us, but the thing is, that doesn’t happen.” 

We know that other gigantic animals com­bat cancer by expressing multiple copies of tumor suppressor genes like p53; elephants express nearly twenty copies of p53. The role tumor suppressor genes play in cetacean can­cer resistance is still fuzzy.

“[Whales] are so big and live such a long life. Why do they have less risk of getting cancer? What are the molecular mechanisms that let them live so long?” asked Martinez.

In a study published in the Proceedings of the Royal Society B in February, Martinez used comparative genomics to get to the bottom of it (4). She examined the evolution of over 1000 tumor suppressor genes in the ances­tors of cetaceans, baleen whales (e.g. bow­head whales), and toothed whales (e.g. orcas and dolphin). Baleen and toothed whales branched off from the original cetacean ancestor over 30 million years ago. Genes related to cell proliferation, DNA damage, breast, lung, and blood cancer were positively selected for in cetaceans and baleen whales.

In addition to the number of gene variants in each ancestor, Martinez calculated gene turnover rate, or the rate of the loss or gain of a particular gene. The higher the turnover rate, the more chance a particular gene will be mutated or duplicated over time. 

The gene turnover rate in the cetacean ancestor was about 2.5-fold higher than other mammals, and even higher in baleen whales. The cetacean ancestor had 71 duplicated tumor suppressor genes; 11 of these genes are involved in processes like cell prolifera­tion and metabolism and link to living longer. 

Interestingly, many of the tumor suppres­sor genes with high turnover rates that were positively selected for over evolution also related to gigantism, meaning that some of the same genes that protect whales against cancer, also made them bigger.

“The discovery of these new molecular variants, including the additional copies of genes, could be the key to reveal new biologi­cal pathways that could lead to the creation of innovative treatments of cancer and aging related diseases,” said Martinez.

Martinez plans to make cell lines with the genetic variants and gene copies she identi­fied to see if the mutations can protect the cells from cancer-causing damage.

One day, she will collect whale samples, but for now she stays at the desk looking at other mammals, particularly cancer resis­tant mammals like the naked mole rat, to see if they share common variants in tumor suppressors.

“I’m working with about 20 mammalian species across the tree of life,” said Martinez.


Wild cancer breaks all the rules

Martinez and Gorbunova are interested in looking at a variety of animals, but some researchers are satisfied with studying just one: Tasmanian devils.

David Hockenberry, a professor in the clinical research division at Fred Hutchinson Cancer Research Center, thinks that studying cancer “in the wild” is a unique opportunity to watch cancer naturally progress.

“[In cancer patients], we immediately try to cut out the tumor or try to treat it with either targeted or cytotoxic chemotherapy. We don’t get to see this sort of natural his­tory,” he said. “These are wild animals. They’re not being treated; the tumors are not being cut out. So you get to just watch it, and you may see [something] that we just don’t [otherwise].”

“I think it’s fascinating and tragic in a way,” he added.

A healthy Tasmanian devil
A Tasmanian devil with tumors spread throughout its body








Hockenberry and Elizabeth Murchison, a professor of comparative oncology and genetics at the University Cambridge, are interested in a type of fatal infectious facial tumor known as Devil Facial Tumor Disease (DFTD) that rapidly spreads between Tas­manian devils. Tasmanian devils are on the brink of extinction due to this tumor. Some conservationists predict that they won’t be here in 30 years.

Hockenberry and Murchison work sepa­rately to understand this strange, infectious tumor and try to learn how to stop it. Some of  their findings may inform our understand­ing of human cancer, especially infectious cancers. Some human viruses such as human papillomavirus (HPV) increase the risk for developing certain cancers. 

“What’s infectious in the Tasmanian devil is the tumor itself,” said Hockenberry. “[The tumor] is quite distinct from the cells of the host animal, so the host animal cells don’t get transformed or infected or any­thing along those lines. It’s the tumor itself that gets transmitted.” 

Tasmanian devils spread these tumors through biting each other in the face, which they do a lot during their social and mating interactions. 

Murchison grew up in Tasmania, so she has extensive experience with Tasmanian devils. She claims they are nothing like Taz from Looney Tunes. 

“They’re actually really beautiful animals when you see them up close in the wild... They tend to be very docile,” said Murchi­son. “You can kind of handle them and check them for tumors while they are just sitting there...I don’t think they would ever con­sider really attacking a person. I think they are just too scared.” 

Her interest in wildlife, especially in Tas­manian devils, started as a child. So when Murchison first heard about DFTD as a graduate student, she knew that she had to learn more to help the dwindling Tasma­nian devil population. 

Like tracking down the primary tumor in metastatic cancer, Murchison wanted to find the original source of this infectious cancer, which metastasizes from host to host. 

Eleven years ago, she reported in Science that DFTD arose from schwann cells, a cell type that insulates peripheral nerves (5). 

Researchers identified a second, distinct clone of DFTD five years ago (6). Murchison identified the origin of the tumor in 2019: it was also derived from schwann cells (7). 

“It was a bit of a surprise,” said Murchi­son. “It seems likely that this particular cell type is particularly vulnerable to producing transmissible cancers in the devils, and why that is, we still don’t really know.” 

Murchison hypothesizes that Tasma­nian devils damage their peripheral nerves through repeated biting, making them more susceptible to schwann cell derived facial tumors. Tasmanian devils have low genetic diversity as well, so positive selection for a mechanism to defend themselves against these tumors is unlikely. 

Human schwannomas share a common genetic profile with DFTD, but not much else. This research may not help scientists understand human cancer, but it should help researchers answer questions about similar infectious cancers in animals like dogs and clams. 

Hockenberry also addresses another open question that may inform human cancer research: How do Tasmanian devil tumors regress? 

Hockenberry’s collaborator, Andrew Storfer, a professor of biology at Washing­ton State University, noticed that some tumors resolved naturally over time. He compared the genetic profile of tumors that did and did not regress using whole genome sequencing (8). 

Storfer and Hockenberry reported last year in the journal Genetics that all tumors that regressed carried a mutation in a gene called RAS11A (9). The point mutation occurred in the 5’ untranslated region, rather than in the coding region of the gene. The mutation did not alter protein function, but rather, turned the gene on in tumors that regressed. 

RAS proteins are key signal transduc­tion proteins that are mutated in 30% of all cancers. RAS11A codes for a poorly char­acterized member of the RAS protein fam­ily. Although its function is unknown, it is silenced in some human colon and prostate cancers. All evidence suggests that RAS11A serves as a tumor suppressor. 

When Storfer and Hockenberry depleted levels of RAS11A in Tasmanian devil tumor cells in vitro, it slowed their growth. 

“Something we are exploring now is whether these cells that have the RAS11A mutation might be acting as winners, and just getting rid of the other cells. And then you’re left with a cell that can’t grow very fast, which would be pretty novel,” said Hockenberry. 

If Hockenberry and his team can find a way to activate RAS11A in tumors actively growing in Tasmanian devils, they could help preserve the species. Only time will tell if targeting RAS11A will have the same therapeutic potential in humans. 


Robert Canter, a professor in the department of surgery at the University of California, Davis, leads a clinical trial to test an immunotherapy for dog cancer.

The cure for cancer might be right under a wet nose 

Dogs are the opposite of wild animals. Their natural habitats are often sun soaked couch­es snuggled up next to their humans. They live in the same environments as humans, share our food, and mirror our physical activity — their gut microbiomes even look like ours. And many dog cancers look geneti­cally similar to our own. 

“Dogs and people are some of the few spe­cies that really outlive their natural lifespan, in part because of modern society,” said Rob­ert Canter, a professor in the department of surgery at the University of California, Davis. “I think that is a big contributor to why can­cer incidence is so high and is such a major cause of death in both these species.” 

Canter and his colleague Robert Rebhun, professor of surgical and radiological sci­ences at the University of California, Davis School of Veterinary Medicine, teamed up to find a new immunotherapy treatment for dog sarcomas such as melanoma and osteosarcomas (10). 

Immunotherapy strengthens the immune system to help stave off cancer. Treatment with the cytokine IL-2 activates T-cells, putting up the body’s defense against cancer. This treatment effectively treats cancers in dogs and humans. 

However, IL-2 immunotherapy isn’t per­fect — the therapy works against itself. One of the major challenges is that it primarily activates regulatory T-cells, which dampen inflammation and promote apoptosis. 

Canter and Rebhun are testing another cytokine, IL-15, as a potential therapeutic in dogs. IL-15 only activates effector T-cells and doesn’t promote activation-induced cell death. It also activates an additional immune cell, natural killer cells, strength­ening the immune response. 

The pair recently showed that IL-15 inha­lation successfully activated both immune cells in dogs (10). 

“We’re seeing some fairly exciting pre­liminary results. Some of the dogs have responded very, very nicely,” said Canter. “[There was] even one dog where the cancer went completely away. and it stayed away for over six months... It’s very encouraging.” 

The team is starting a phase II clinical trial to validate their results. This study will be multi-institutional, including other major veterinary schools throughout the country and 40 bushy-tailed participants. 

If everything goes well in the dog clinical trials, Canter plans to transfer this approach to humans. While Rebhun hopes that the treatment will translate to humans, he also wants it to benefit dogs. 

“What can we learn from human oncology and cancer biology? Can we apply that to the dog and improve diagnosis and therapy in the dog?” asked Rebhun. “On the flip­side of that, can we use naturally occurring cancer in dogs...to study or improve cancer treatments in people?” 

Using their immunotherapy in humans will require some tweaking first. Human IL-15 and dog IL-15 are not the same. In order to do this in humans, they need to iso­late the human form. But Canter is ready to overcome any obstacles. 

“I think there is an immediate applica­tion of IL-15 in humans (knock on wood) if our results look good,” said Canter. “Some people have even already said to us that we should do a human trial.”


Reference 

1. Ahmad F.B. and Anderson R.N. The leading causes of death in the US for 2020. JAMA. (2021).

2. Katzourakis A. et al. Larger mammalian body size leads to lower retroviral activity. PLOS Pathogens. (2014).

3. Seluanov A., et al. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole rats. PNAS. 106 (46): 19352-19357. (2009). 

4. Tejada-Martinez D., et al. Positive selection and gene duplications in tumour suppressor genes reveal clues about how cetaceans resist cancer. Proc. R. Soc. B. (2021).

5. Murchison E.P., et al. The Tasmanian devil transcriptome reveals schwann cell origins of a clonally transmissible cancer. Science. 327 (5961): 84-87. (2010).

6. Pye R.J., et al. A second transmissible cancer in Tasmanian devils. PNAS. 113 (2): 374-379. (2015).

7. Patchett A.L., et al. Two of a kind: transmissible schwann cell cancers in the endangered Tasmanian devil. Cell. and Molec. Life Sci. 77: 1847-1858. 2019.

8. Margres M.J., et al. The genomic basis of tumor regression in Tasmanian devils. Genome Biol. Evol. 10 (11): 3012-3025. (2018).

9. Margres M.J., et al. Spontaneous tumor regression in Tasmanian devils associated with RAS11A activation. GENETICS. 215 (4): 1143-1152. (2020).

10. Judge S.J., et al. Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas. Journal for ImmunoTherapy of Cancer. (2020).

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