̽��ֱ�� of Cambridge - Tasmanian devils

Human anti-cancer drugs could help treat transmissible cancers in Tasmanian devils

cjb250 — Mon, 09 Apr 2018 15:57:27 +0000

̽��ֱ��research also found that the two Tasmanian devil transmissible cancers are very similar to each other, and likely both arose due to susceptibilities inherent to the devils themselves.

Tasmanian devils are marsupial carnivores endemic to the Australian island of Tasmania. ̽��ֱ��species is considered endangered due to devil facial tumour 1 (DFT1), a cancer that is passed between animals through the transfer of living cancer cells when the animals bite each other. DFT1 causes grotesque and disfiguring facial tumours, which usually kill affected individuals.

̽��ֱ��DFT1 cancer first arose in a single individual devil several decades ago, but rather than dying together with this devil, the cancer survived by ‘metastasising’ into different devils. Therefore, the DNA of the devils’ tumour cells is not their own DNA, but rather belongs to the individual devil that first gave rise to DFT1 all those years ago. Remarkably, DFT1 cells can escape the devils’ immune systems despite being in essence a foreign body.

̽��ֱ��DFT1 cancer was first observed in north-east Tasmania in 1996, but has subsequently spread widely throughout the island, causing significant declines in devil populations.

In 2014, routine diagnostic screening revealed a second transmissible cancer in Tasmanian devils, devil facial tumour 2 (DFT2), which causes facial tumours indistinguishable to the naked eye from those caused by DFT1, and which is probably also spread by biting. However, analysis showed that the two types of cancer differ at a biological level, and whereas DFT1 first arose from the cells of a female devil, DFT2 appears to have first arisen from a male animal. For now, DFT2 appears to be confined to a peninsula in Tasmania’s south-east.

“ ̽��ֱ��discovery of a second transmissible cancer in Tasmanian devils was a huge surprise,” says Dr Elizabeth Murchison from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge. “Other than these two cancers, we know of only one other naturally occurring transmissible cancer in mammals – the canine transmissible venereal tumour in dogs, which first emerged several thousand years ago.”

In fact, outside of mammals, only five transmissible cancers have been observed, all of which cause leukaemia-like diseases in clams and other shellfish.

“ ̽��ֱ��scarcity of transmissible cancers suggests that such diseases emerge rarely,” she adds. “Before 1996, no one had observed them in Tasmanian devils, so finding two transmissible cancers in Tasmanian devils in just eighteen years was very surprising.”

In order to see whether the devil transmissible cancers are caused by external factors or whether the animals were just particularly susceptible to developing these cancers, a research team led by Dr Murchison analysed the genetic profiles of DFT1 and DFT2 tumours taken from a number of Tasmanian devils. ̽��ֱ��results are published today in the journal Cancer Cell.

̽��ֱ��team found striking similarities in tissues-of-origin, genetics, how the cancer cells mutate, and possible drug targets. This implies that the two tumours belong to the same cancer type and arose via similar mechanisms.

̽��ֱ��team studied the genetic and physical features of the tumours, and compared the two lineages with each other and with human cancers. In doing so, they identified an important role in the tumours for particular types of molecules known as receptor tyrosine kinases (RTKs) in sustaining growth and survival of DFT cancers.

Importantly, drugs targeting RTKs have already been developed for human cancer, and the researchers showed that these drugs efficiently stopped the growth of devil cancer cells growing in the lab. This leads to hope that it may be possible to use these drugs to help Tasmanian devils.

First author of the study, Maximilian Stammnitz, adds: “Altogether, our findings suggest that transmissible cancers may arise naturally in Tasmanian devils. We found no DNA-level evidence of these cancers being caused by external factors or infectious agents such as viruses. It seems plausible that similar transmissible cancers may have occurred in the past, but escaped detection, perhaps because they remained in localised populations, or because they existed prior to the arrival of Europeans in Tasmania in the nineteenth century.”

Why Tasmanian devils should be particularly susceptible to the emergence of DFTs is not clear. However, devils bite each other frequently around the facial area, often causing significant tissue injury. Given the important role for RTK molecules in wound healing, the researchers speculate that DFT cancers may arise from errors in the maintenance of proliferative cells involved in tissue repair after injury.

“When fighting, Tasmanian devils often bite their opponent’s face, which may predispose these animals to the emergence of this particular type of cancer via tissue injury,” adds Stammnitz. “As biting occurs on the face, this would simultaneously provide a route of cell transmission.”

̽��ֱ��researchers say it is also possible that human activities may have indirectly increased the risk of the emergence or spread of transmissible devil facial tumours (DFTs) in recent years. For instance, it is possible that some modern land use practices may have provided favourable conditions for devils, leading to an increase in local population densities of devils, and to greater competition, interactions and fights between animals, which may in turn have raised probabilities of DFTs arising or spreading. Alternatively, early persecution of devils by European colonists may have additionally contributed to this species' documented low genetic diversity, a possible risk factor for disease spread and the ability of DFTs to escape the immune system.

̽��ֱ��researchers also identified deletions in DFT1 and in DFT2 in genes involved in recognition of cancer cells by the immune system. This may help explain how these cancers escape the immune system.

“ ̽��ֱ��story of Tasmanian devils in recent years has been a very concerning one,” says Dr Murchison. “This study gives us optimism that anti-cancer drugs that are already in use in humans may offer a chance to assist with conservation efforts for this iconic animal.”

̽��ֱ��research was funded by Wellcome, the National Science Foundation, Save the Tasmanian Devil Appeal, Leverhulme Trust, Cancer Research UK and Gates Cambridge Trust.

Reference
Stammnitz, M.R., et al. (2018). ̽��ֱ��origins and vulnerabilities of two transmissible cancers in Tasmanian devils. Cancer Cell 33(4), 607-619.

Transmissible cancers are incredibly rare in nature, yet have arisen in Tasmanian devils on at least two separate occasions. New research from the ̽��ֱ�� of Cambridge identifies key anti-cancer drugs which could be trialled as a treatment for these diseases, which are threatening Tasmanian devils with extinction.

This study gives us optimism that anti-cancer drugs that are already in use in humans may offer a chance to assist with conservation efforts for this iconic animal

Elizabeth Murchison

Could cancer drugs help save the Tasmanian devil?

Mathias Appel

Tasmanian devil

Researcher profile: Maximilian Stammnitz

One of Maximilian Stammnitz’s best memories at Cambridge has been his encounter with Tasmanian devils on a field trip to Tasmania in 2016. “There is nothing more exciting than examining actual devils in the wild – they are truly majestic animals!” he says.

Stammnitz is a Gates Cambridge Scholar at Cambridge’s Department of Veterinary Medicine. Originally from “Germany's sunniest spot: Heidelberg”, he came to Cambridge to join the Computational Biology MPhil program at the Department of Applied Mathematics and Theoretical Physics in 2014.

“This course provides fascinating opportunities to study biology through a big data lens, and to learn about vastly emerging genomics technologies from experts in the field,” he says. “ ̽��ֱ��DNA-level expertise and collaboration at Cambridge surrounding topics of genetics, evolution, medicine and computational data analysis is breath-taking.”

It was a seminar by Elizabeth Murchison on transmissible cancers that caught his imagination, however, and he subsequently joined her group at Veterinary Medicine for a summer internship, and then as a PhD student and Gates Cambridge Scholar. ̽��ֱ��ultimate aim of his work is to save the largest carnivorous marsupial on the planet, but by studying the fundamental processes of cancer development in Tasmanian devils, his work could help us understand better how cancer develops in humans.

“I spend most of my working days behind a computer screen, processing and analysing large volumes of DNA and RNA sequencing data from Tasmanian devil tumour biopsies,” he says. “Occasionally, I also do molecular biology experiments in the 'wet lab', to validate our computational results or to establish testing protocols for the devils.”

It isn’t all about work, though. “Over the past year, I have been the captain of our university's Blues men's volleyball team and co-founded PuntSeq, a citizen science project aiming at cost-effective pathogen surveillance of our house river Cam's water,” he says.

“My biggest challenge of living here is to balance truly focused work life and quiet time with the many inspiring distractions that wait behind the corners of Cambridge's old walls. It’s a luxury problem to have as a PhD student.”

Follow Maximilian Stammnitz on Twitter @DevilsAdvoMax

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Second contagious form of cancer found in Tasmanian devils

cjb250 — Mon, 28 Dec 2015 20:00:13 +0000

̽��ֱ��discovery, published in the journal Proceedings of the National Academy of Science, calls into question our current understanding of the processes that drive cancers to become transmissible.

Tasmanian devils are iconic marsupial carnivores that are only found in the wild on the Australian island state of Tasmania. ̽��ֱ��size of a small dog, the animals have a reputation for ferocity as they frequently bite each other during mating and feeding interactions.

In 1996, researchers observed Tasmanian devils in the north-east of the island with tumours affecting the face and mouth; soon it was discovered that these tumours were contagious between devils, spread by biting. ̽��ֱ��cancer spreads rapidly throughout the animal’s body and the disease usually causes the death of affected animals within months of the appearance of symptoms. ̽��ֱ��cancer has since spread through most of Tasmania and has triggered widespread devil population declines. ̽��ֱ��species was listed as endangered by the International Union for Conservation of Nature in 2008.

To date, only two other forms of transmissible cancer have been observed in nature: in dogs and in soft-shell clams. Cancer normally occurs when cells in the body start to proliferate uncontrollably; occasionally, cancers can spread and invade the body in a process known as 'metastasis'; however, cancers do not normally survive beyond the body of the host from whose cells they originally derived. Transmissible cancers, however, arise when cancer cells gain the ability to spread beyond the body of the host that first spawned them, by transmission of cancer cells to new hosts.

Now, a team led by researchers from the ̽��ֱ�� of Tasmania, Australia, and the ̽��ֱ�� of Cambridge, UK, has identified a second, genetically distinct transmissible cancer in Tasmania devils.

“ ̽��ֱ��second cancer causes tumours on the face that are outwardly indistinguishable from the previously-discovered cancer,” said first author Dr Ruth Pye from the Menzies Institute for Medical Research at the ̽��ֱ�� of Tasmania. “So far it has been detected in eight devils in the south-east of Tasmania.”

“Until now, we’ve always thought that transmissible cancers arise extremely rarely in nature,” says Dr Elizabeth Murchison from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge, a senior author on the study, “but this new discovery makes us question this belief.

"Previously, we thought that Tasmanian devils were extremely unlucky to have fallen victim to a single runaway cancer that emerged from one individual devil and spread through the devil population by biting. However, now that we have discovered that this has happened a second time, it makes us wonder if Tasmanian devils might be particularly vulnerable to developing this type of disease, or that transmissible cancers may not be as rare in nature as we previously thought.”

Professor Gregory Woods, joint senior author from the Menzies Institute for Medical Research at the ̽��ֱ�� of Tasmania, adds: “It’s possible that in the Tasmanian wilderness there are more transmissible cancers in Tasmanian devils that have not yet been discovered. ̽��ֱ��potential for new transmissible cancers to emerge in this species has important implications for Tasmanian devil conservation programmes.”

̽��ֱ��discovery of the second transmissible cancer began in 2014, when a devil with facial tumours was found in south-east Tasmania. Although this animal’s tumours were outwardly very similar to those caused by the first-described Tasmanian devil transmissible cancer, the scientists found that this devil’s cancer carried different chromosomal rearrangements and was genetically distinct. Since then, eight additional animals have been found with the new cancer in the same area of south-east Tasmania.

̽��ֱ��research was primarily supported the Wellcome Trust and the Australian Research Council, with additional support provided by Dr Eric Guiler Tasmanian Devil Research Grants and by the Save the Tasmanian Devil Program.

For more information about the research into Tasmanian devils, see T is for Tasmanian Devil.

Reference
Pye, RJ et al. A second transmissible cancer in Tasmanian devils. PNAS; 28 Dec 2015

Transmissible cancers – cancers which can spread between individuals by the transfer of living cancer cells – are believed to arise extremely rarely in nature. One of the few known transmissible cancers causes facial tumours in Tasmanian devils, and is threatening this species with extinction. Today, scientists report the discovery of a second transmissible cancer in Tasmanian devils.

Until now, we’ve always thought that transmissible cancers arise extremely rarely in nature, but this new discovery makes us question this belief

Elizabeth Murchison

Gopal Vijayaraghavan

Tassie devil orphan

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Attribution

Tasmanian Devils and the transmissible cancer that threatens their extinction

amb206 — Wed, 14 Oct 2015 11:05:42 +0000

Scroll to the end of the article to listen to the podcast.

In 1996 a wildlife photographer working in a remote part of Tasmania noticed a ‘Tassie devil’ (the affectionate name for the Tasmanian devil) with a tumour on its face. He assumed that the animal’s facial disfigurement was a one-off – but within a year he spotted another devil with a similar problem. He notified the authorities and, as increasing numbers of affected devils were seen, it was established that the animals were suffering from a wave of devastating facial tumours.

Ten years after the first tumour was spotted, scientists revealed that the lesions weren’t ordinary tumours. They were caused by a transmissible cancer – an extremely rare type of disease, in which living cancer cells are physically transmitted between animals. Only three transmissible cancers are known in nature, and these affect dogs, clams and Tasmanian devils respectively. In the case of devils, the cancer cells are thought to be transmitted by biting.

Once they have acquired the cancer, devils usually live just a matter of months. No treatment exists. As the number of sightings of afflicted animals continued to escalate, with the disease moving across the island from east to west, it became clear that the Tasmanian devil was threatened with extinction.

Dr Elizabeth Murchison, a specialist in comparative oncology and genetics at the ̽��ֱ�� of Cambridge’s Department of Veterinary Medicine, was brought up in Tasmania. ̽��ֱ��presence of Tasmanian devils – which are the emblem of the Tasmanian state – was part of her rural childhood. Devils are scavengers and, by disposing of dead animals, they provide a useful service as the ‘garbage bins of the bush’.

Murchison studied genetics and biochemistry at the ̽��ֱ�� of Melbourne, and then studied for her PhD in molecular biology at Cold Spring Harbor Laboratory, New York. Her interest in solving the puzzle of the tumours began in 2006 when she came across a roadkill devil with a tumour in a wild area of Tasmania. This confronting finding triggered her desire to understand this strange disease.

Her specialism is cancer genetics; her research focuses on developing an understanding of the evolution of the DNA of transmissible cancer by tracing it backwards in time to track the steps by which a normal cell mutates to become a cancerous one.

In 2012, while working at the Sanger Institute, near Cambridge, Murchison led a collaborative group of scientists using new DNA sequencing technologies to unlock the Tasmanian devil genome, as well as the genome of the devils’ transmissible cancer. This research led to the discovery that the Tasmanian devil cancer probably emerged relatively recently in a single female Tasmanian devil. ̽��ֱ��cells derived from this cancer have continued to survive by “metastasising” through the Tasmanian devil population.

More recently, Murchison has concentrated on understanding the genetic differences between tumours occurring in different Tasmanian devils. Although tumours in all Tasmanian devils are a “clone”, derived from the same original animal, the cancer lineage has diverged and acquired new mutations during its spread through the devil population.

This work requires close collaboration with many scientists, especially those back in her native Tasmania. She says: “I wake up to emails from the other side of the world, updating me on the progress of field work back in Tasmania. We skype regularly because working closely together as an interdisciplinary team is the best way to try to understand this disease and help the devils as soon as possible.”

In addition to working on the Tasmanian devil, Murchison’s group studies canine transmissible venereal tumour (CTVT). CTVT is a sexually transmitted genital cancer, spread by the transfer of living cancer cells between dogs. In contrast to the devil cancer, which emerged relatively recently, CTVT probably emerged thousands of years ago. ̽��ֱ��disease has now spread widely and affects dogs around the world. Murchison’s group has recently sequenced the genome of CTVT, and this work has shed light on the evolution of a unique cancer.

One of the most disquieting aspects of transmissible cancers is the fact that they are, effectively, parasites. Once the devil cancer cells are introduced to a new host by means of a bite, they go undetected by the devil’s immune system and thus flourish, eventually killing the animal. By sequencing samples of DNA taken from the devil cancer from 2003 onwards, Murchison is trying to understand how this cancer evolved and changed with time. Her research makes a valuable contribution to the potential development of a vaccine or other therapy to protect devils against the disease.

Over the past decade, the Tasmanian authorities have worked hard to safeguard the future of the Tasmanian devil. An ‘insurance’ population of healthy devils has been spread among Australian parks and zoos. Most recently, a colony of unaffected devils has been established on Maria Island, a national park off the coast of eastern Tasmania.

“Research into this devastating disease in Tasmanian devils is starting to illuminate the underlying processes that caused this unusual disease and promoted its transmission. We hope that our research may also help us to understand basic processes that underlie cancer evolution more generally, including in humans. But, of course, we are motivated by the goal that our research will help to protect this unique and iconic marsupial from extinction,” said Murchison.

Next in the Cambridge Animal Alphabet: U is for an animal used in heraldry since the 15th century and in recipes for anti-poison since the 1700s.

Have you missed the series so far? Catch up on Medium here.

Inset images: Tasmanian devil with facial tumours (Elizabeth Murchison); Video clips courtesy of the Save the Tasmanian Devil Program , DPIPWE; Tasmanian devil (Joe Le Nevez).

The Cambridge Animal Alphabet series celebrates Cambridge's connections with animals through literature, art, science and society. Here, T is for Tasmanian Devil and the researchers studying the transmissable cancer that threatens these marsupials with extinction.

We are motivated by the goal that our research will help to protect this unique and iconic marsupial from extinction

Elizabeth Murchison

Tasmanian Devil

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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