The Tasmanian devil (Sarcophilus harrisii), the world’s largest living carnivorous marsupial, is threatened with extinction by a horizontally transmitted cancer termed devil facial tumor disease (DFTD). Using an integrative systems-wide approach, a team of researchers in Austria has identified molecular mechanisms that are crucial for DFTD’s transmissibility. Their results appear in the journal Cancer Cell.
Tasmanian devil (Sarcophilus harrisii). Image credit: J.J. Harrison / CC BY-SA 3.0.
Tumors usually grow exclusively in the organism where their cell of origin derives from.
The same applies for human cancers: apart from some rare cases, like the accidental transmission by a cut during surgery, there are no reports of contagious cancer cells.
A multitude of molecular safety measures of the immune system are responsible for rejecting and destroying any foreign tissue. An exception to this nearly universal rule exists among Tasmanian devils.
For two decades, DFTD has been spreading at a rapid pace among the animals and has killed, according to current estimates around 90% of the wild population. Peculiarly, the cancer cells are transmitted from one Tasmanian devil to the other by bites.
All collected tumor samples are genetically nearly identical and derive presumably from a single cell of origin.
How this cancer became transmissible and by what means it escapes the immune system of its otherwise healthy hosts has puzzled scientists since the discovery of the mysterious disease.
A team of scientists from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Vienna University of Veterinary Medicine has now solved an important part of the puzzle.
Kosack et al identify the ERBB-STAT3 signaling axis as a central molecular driver of Tasmanian devil transmissible facial tumors. Inhibition of ERBB or STAT3 prevents tumor growth in xenograft models and restores MHC class I expression, suggesting a chemo-immunotherapeutic strategy to save Tasmanian devils. Image credit: Kosack et al, doi: 10.1016/j.ccell.2018.11.018.
In their latest study, the researchers identified molecular mechanisms that are crucial for the transmissibility of DFTD.
“We found that receptor molecules on the surface of the cancer cells, so-called ERBB receptors, show massively increased activity. Those receptors trigger a biochemical chain reaction within the cells that eventually activates STAT3 proteins, transcription factors that alter the cell’s genetic program,” they said.
“The result is an extensive rebuild of the cell: the number of molecules serving as identification for the immune system is reduced, while at the same time proliferation is accelerated and factors for metastasis of the tumor cells are produced.”
“Our experiments show for the first time that the excessive activation of ERBB receptors and STAT3 proteins play a key role in DFTD’s transmissibility,” said study first author Dr. Lindsay Kosack, a researcher at the CeMM.
“Above that, we showed in further experiments that the inhibition of ERBB receptors with a drug can selectively kill the cancer cells.”
“This could play an important role for the treatment of the disease, before the Tasmanian devil becomes extinct.”
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Lindsay Kosack et al. 2019. The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease. Cancer Cell 35 (1): 125-139; doi: 10.1016/j.ccell.2018.11.018
