Why do some animals catch cancer?

The vast majority of cancers are a threat from within, as our own cells multiply uncontrollably to form a tumour. But contagious cancer cells do more than that. They act like a pathogen or parasite, and can infect multiple hosts. In the case of the Tasmanian devils, the cancer is passed from one animal to the next as they bite each other during aggressive social interactions. The disease is decimating Tasmanian devil populations, which are listed as ‘endangered’ on the IUCN Red List.

Like all cancers, transmissible ones are caused by changes, or mutations, in DNA. The mutations accumulate over time, and enable the cells to grow unchecked. Studying the mutations in cancer genomes can reveal their origins, characteristics and ongoing evolution.

New research by scientists at the University of Cambridge, the Universidade de Santiago de Compostela, Spain and the Wellcome Sanger Institute has mapped the emergence and characteristics of transmissible cancers in Tasmanian devils and in marine cockles. Their work sheds light on the biology of these unusual cells.

Transmissible cancers are rare, but Tasmanian devils have two; devil facial tumour disease (DFT) 1 and DFT2. DFT1 was first identified in the 1990s, and is now widespread. It is usually fatal. DFT2 is also lethal, though it arose more recently. It was first seen in 2014, and so far is more limited in its spread. The fact that two cancers exist in one species is ‘incredible’, according to Elizabeth Murchison, Professor of Comparative Oncology and Genetics at University of Cambridge, and an expert in the disease. She has led research into transmissible cancers for over a decade, including sequencing the Tasmanian devil genome for the first time¹ and their transmissible cancer cells for the first time². Her work uncovered DFT1’s origins in a single female animal, which they termed ‘The Immortal Devil’, as its DNA lives on. Professor Murchison's team has now studied the genomes of both of DFT2 and DFT1 in new detail, unravelling their ongoing evolution.

To study the cancer cells, the team first created a new, high-quality reference genome - a map of the entire DNA sequence of the devil. Their work bridged more than 35,000 gaps in the previously available sequence.

“High quality reference genomes are vitally important for genetic studies, including those in wildlife conservation. For the genomes of Tasmanian devil and Cockle, both assemblies were generated using long reads from Oxford Nanopore Technologies and the assemblies have been released to the scientific community.”

Dr Zemin Ning,
an author for both studies from the Wellcome Sanger Institute

Following the reference genome, the team analysed hundreds of thousands of DNA changes from 78 DFT1 and 41 DFT2 tumour biopsies collected throughout Tasmania.

By comparing DNA mutations from recently collected tumours to those collected many years ago, they discovered that the changes accumulate at a constant rate in both DFT1 and DFT2. These cancers each acquire a few hundred mutations per year, similar to human cancers.

The steady mutation rate enabled the researchers to use the sequences to construct a phylogenetic tree, much like a family tree, and to build a picture of how the disease has evolved. This showed that DFT1 arose in the 1980s, up to a decade before it was first seen in 1996. Their work shows there was an explosive transmission event shortly after it emerged, where an infected devil transmitted its tumour to at least six others. The team also found a case where the cancer was transmitted from a mother to a young in the pouch – the first time this had been seen for the disease.

The team found that DFT2 arose in 2011, only three years before its 2014 discovery. It is not widespread at the moment, but they showed that it is evolving quickly. Both cancers have ongoing, large-scale changes occurring in their genome. DFT2 could be disaster for the animals.

“I come from Tasmania and love Tasmanian devils – they have a special place in my heart. Transmissible cancers pose an unprecedented and unpredictable threat to Tasmanian devils.”

Professor Elizabeth Murchison,
lead author of the study, University of Cambridge³

Like the cancers in Tasmanian devils, transmissible cancers in cockles are spread by living cancer cells, which are passed from one animal to the next. It is thought that sea creatures catch cancer during filter feeding, as free-floating cells in the water pass by.

The cancers that infect cockles are termed bivalve transmissible neoplasia (BTN). The cancer cells accumulate in the animals’ fluids and organs, causing a disease much like leukaemia. Infection is usually fatal. Eight BTNs have been identified so far. One, in Cerastoderma edule, the common cockle, was first seen 40 years ago in Ireland.

Researchers at Universidade de Santiago de Compostela in Spain and the Sanger Institute studied BTN in common cockles, unravelling its genome and evolution for the first time.

Like in the Tasmanian devil study, the team first determined the reference genome sequence of the cockle species. The researchers then collected thousands of specimens at 36 locations from 11 countries, along the Atlantic coasts of Europe and North Africa.

The team then sequenced cancer cells from 61 animals with the disease. They compared the data and catalogued the genomic variations in the cancers.

Combining methods including microscopy, sequencing of whole genomes and sequencing the active genes, their study illuminates the evolutionary history of marine leukaemia.

While it is not possible to precisely estimate the age of cockle BTN, their work suggests that these cancers emerged centuries or even millennia ago.

Chiming with previous research, they found that the BTN tumour genomes are highly unstable. The number and size of chromosomes varied between the different samples of the same cancer. The team showed that this instability was probably activated by a whole-genome duplication, early in the cancer’s evolution. There is also evidence that the cells chromosome structure continues to be unstable during cell division.

This instability is in stark contrast with the transmissible cancers in Tasmanian devils, which show a stable genome in terms of chromosome number over time. The researchers conclude that a stable genome is probably not needed for the long-term survival of transmissible cancers.

“Our study showed that the cells in these cockle tumours contain highly variable amounts of genetic material, which is very unusual compared to other types of cancer. These cancers have been undergoing extreme chromosomal changes and continuous genetic reorganisation, probably for hundreds or thousands of years, which challenges the theory that cancers require stable genomes to survive long-term.”

Dr Daniel Garcia-Souto,
previously based at the Wellcome Sanger Institute and currently at the Universidade de Santiago de Compostela

The researchers hope that studying how BTN cells overcome the effects of genomic instability will have implications for understanding all forms of cancer, including in humans.

It is not yet clear how transmissible cancers can continue to exist in multiple hosts. Usually, the immune system can detect any invading cells or tissue as ‘non-self’, and destroy them. Very little is known about how this process works in invertebrates like cockles, which lack an adaptive immune system.

Professor Murchison’s team has found clues as to how the Tasmanian devil’s cancer may bypass the immune system, but further studies will be required to understand how the cancer escapes.

The team’s work has highlighted how vulnerable the devils are to both DFT1 and DFT2, which continue to evolve and pose a critical threat to the species.

[1] https://www.sanger.ac.uk/news_item/2010-09-16-completed-genome-is-first-step-to-tackling-tasmanian-devil-facial-tumours/

[2] https://www.sanger.ac.uk/news_item/2012-02-16-preventing-the-devil-s-downfall/

[3] https://www.sanger.ac.uk/news_item/evolution-of-two-contagious-cancers-affecting-tasmanian-devils-underlines-unpredictability-of-disease-threat/