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Devil May Care: Tasmanian Devil Evolution in the Face of Lethal, Contagious Cancer
Cancers are clonal cell lineages that emerge due to the acquisition of genetic mutations that promote aberrant proliferation and survival. Cancer is the natural consequence of prolonged life expectancy; longer life allows for the accumulation of mutations that can lead to cancer. While cancer is a significant burden on human society, we are lucky at least in that no human cancers are naturally transmissible, meaning cancer cannot be “caught” from affected human individuals. Cells from one individual are different enough from cells of other individuals that, when transferred, they can be identified as foreign invaders and can be rejected.

Beatrice the Biologist
Tasmanian Devils aren’t so lucky. A particular Tasmanian Devil cancer (devil facial tumor disease, or DFTD) is highly contagious primarily due to its capacity to evade immune surveillance1. Tumors grow on the faces and mouths of infected Devils, frequently metastasize, and usually cause death within a few months due to metabolic starvation, secondary infection, or organ failure following metastasis2. Aggressive behavior between Devils during mating and feeding, characterized by bites and scratches to the face, transmits tumor cells from one Devil to the next3. As a result, the Devil population has been decimated over the last 20 years, with some dense populations suffering 90-100% mortality4. Luckily, data suggests that the Devil population is evolving under pressure from this lethal disease, providing a possible solution to the endangerment of the largest carnivorous marsupial in the world. Tasmanian Devil Facial Tumour Disease
Devil Facial Tumour Disease Decline
The Tasmanian Devil population has suffered dramatic declines since the first incidence of DFTD. Data from DevilArk.
DFTD was first observed in Tasmanian Devils in northeastern Tasmania in 1996, and has spread from east to west over the last two decades. Genetic analysis of DFTD tumors isolated from distinct Devils across Tasmania indicates that they derived from a single, female Devil cell on an isolated peninsula, and acquired successive mutations, giving rise to distinct subtypes, as they swept across the country5. The DFTD tumor is believed to be of neural crest origin6, as tumor cells express multiple Schwann cell markers, such as myelin basic protein (MBP), periaxin (PRX), peripheral myelin protein 22 (PMP22), and myelin protein zero (MPZ)7. Despite the fact that in vitro and in vivo data suggests that Devils can mount competent cellular and humoural immune responses, they cannot reject the transferred tumor cells1,8. As such, it was initially presumed that Devils were susceptible to the allograft transplantation of these tumors cells due to the lack of genetic diversity within the Devil population3. That is, the Devil population demonstrates a paucity of genetic diversity in Class I MHC (MHC I) alleles9, which code for proteins expressed on the cell surface of all cells and are critical to the recognition of self. This means that a host might mistakenly identify transferred tumor cells as self cells. However, genetically diverse Devils contracted tumors, indicating that host genetics are not responsible for the spread of disease10.
Instead, it was later determined that the tumor cells themselves can escape immune detection. That is, tumor cells down-regulate MHC I, thereby preventing the immune system from recognizing the invading cells11, 12. Interestingly, DFTD, which is one of only three known contagious cancers, is not the only contagious cancer to manipulate MHC I expression for immune evasion.  Canine Transmissible Venereal Tumour (CTVT), which is a sexually-transmitted, contagious allograft that emerged thousands of years ago in ancient dog breeds or wolves13, also down-regulates MHC I during its initial growth stage. However, unlike DFTD, CTVT enters a regression phase, where it up-regulates MHC I and induces an immune response14. In this way, the long periods of homeostasis between tumor and immune response allow survival of the host and ample time for the tumor to be passed to other dogs.

Immense Immunology Insight.
While the situation seems pretty dire for the Tasmanian Devil, all is not lost. New data15 suggests that the Devil population is evolving in as little as six generations, under the pressure of this lethal tumor. By sequencing 294 Tasmanian Devils from three locations across Tasmania, researchers identified two genomic regions that were undergoing rapid genetic changes. These two regions contain seven protein-encoding genes, five of which are associated with cancer risk or immune function. These five genes include CD90, a membrane protein involved in the regulation of a variety of cell-cell interactions including immune system function, cell adhesion and tumor suppression16, and CD146, a cell surface protein whose expression has been, among other things, associated with pro-inflammatory T cells17. Genetic variability in these regions is unlikely to have occurred by chance, and therefore suggests that changes in Devil immune response genes are being selected for, presumably under pressure from DFTD. Given the roles of CD90 and CD146 in immune signaling and immune response, it is possible that the Devils are acquiring the capacity to recognize and counteract tumor growth. As such, it is exciting to think that the Devil population could be rescued through breeding to these new mutants. Do you study Tasmanian Devils? Work with DFTD or another contagious cancer? Let us know at tech@biolegend.com!

Jeff Goldblum, Jurassic Park. Universal Pictures.
References:
  1. Immunology of a Transmissible Cancer Spreading among Tasmanian Devils.
  2. Allograft theory: Transmission of devil facial-tumour disease.
  3. Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial.
  4. Life-history change in disease-ravaged Tasmanian devil populations.
  5. Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer
  6. The Immunohistochemical Characterization of Devil Facial Tumor Disease (DFTD) in the Tasmanian Devil (Sarcophilus harrisii)
  7. The Tasmanian Devil Transcriptome Reveals Schwann Cell Origins of a Clonally Transmissible Cancer
  8. Assessment of cellular immune responses of healthy and diseased Tasmanian devils (Sarcophilus harrisii)
  9. The role of the Major Histocompatibility Complex in the spread of contagious cancers
  10. Allorecognition in the Tasmanian Devil (Sarcophilus harrisii), an Endangered Marsupial Species with Limited Genetic Diversity
  11. A tale of two tumours: Comparison of the immune escape strategies of contagious cancers
  12. Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer
  13. Clonal Origin and Evolution of a Transmissible Cancer
  14. Interactions of host IL-6 and IFN-γ and cancer-derived TGF-β1 on MHC molecule expression during tumor spontaneous regression
  15. Rapid evolutionary response to a transmissible cancer in Tasmanian devils
  16. Wikipedia CD90
  17. MCAM-expressing CD4+ T cells in Peripheral Blood Secrete IL-17A and are Significantly Elevated in Inflammatory Autoimmune Diseases
Contributed by Sarah Puhr, PhD.
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