In vitro competition between two transmissible cancers and potential implications for their host, the Tasmanian devil.

Since the emergence of a transmissible cancer, devil facial tumour disease (DFT1), in the 1980s, wild Tasmanian devil populations have been in decline. In 2016, a second, independently evolved transmissible cancer (DFT2) was discovered raising concerns for survival of the host species. Here, we applied experimental and modelling frameworks to examine competition dynamics between the two transmissible cancers in vitro. Using representative cell lines for DFT1 and DFT2, we have found that in monoculture, DFT2 grows twice as fast as DFT1 but reaches lower maximum cell densities. Using co-cultures, we demonstrate that DFT2 outcompetes DFT1: the number of DFT1 cells decreasing over time, never reaching exponential growth. This phenomenon could not be replicated when cells were grown separated by a semi-permeable membrane, consistent with exertion of mechanical stress on DFT1 cells by DFT2. A logistic model and a Lotka-Volterra competition model were used to interrogate monoculture and co-culture growth curves, respectively, suggesting DFT2 is a better competitor than DFT1, but also showing that competition outcomes might depend on the initial number of cells, at least in the laboratory. We provide theories how the in vitro results could be translated to observations in the wild and propose that these results may indicate that although DFT2 is currently in a smaller geographic area than DFT1, it could have the potential to outcompete DFT1. Furthermore, we provide a framework for improving the parameterization of epidemiological models applied to these cancer lineages, which will inform future disease management.

The differentiation state of the Schwann cell progenitor drives phenotypic variation between two contagious cancers.

Contagious cancers are a rare pathogenic phenomenon in which cancer cells gain the ability to spread between genetically distinct hosts. Nine examples have been identified across marine bivalves, dogs and Tasmanian devils, but the Tasmanian devil is the only mammalian species known to have given rise to two distinct lineages of contagious cancer, termed Devil Facial Tumour 1 (DFT1) and 2 (DFT2). Remarkably, DFT1 and DFT2 arose independently from the same cell type, a Schwann cell, and while their ultra-structural features are highly similar they exhibit variation in their mutational signatures and infection dynamics. As such, DFT1 and DFT2 provide a unique framework for investigating how a common progenitor cell can give rise to distinct contagious cancers. Using a proteomics approach, we show that DFT1 and DFT2 are derived from Schwann cells in different differentiation states, with DFT2 carrying a molecular signature of a less well differentiated Schwann cell. Under inflammatory signals DFT1 and DFT2 have different gene expression profiles, most notably involving Schwann cell markers of differentiation, reflecting the influence of their distinct origins. Further, DFT2 cells express immune cell markers typically expressed during nerve repair, consistent with an ability to manipulate their extracellular environment, facilitating the cell's ability to transmit between individuals. The emergence of two contagious cancers in the Tasmanian devil suggests that the inherent plasticity of Schwann cells confers a vulnerability to the formation of contagious cancers.

Devil Facial Tumours: Towards a Vaccine.

The Tasmanian devil is the only mammalian species to harbour two independent lineages of contagious cancer. Devil facial tumour 1 (DFT1) emerged in the 1990s and has caused significant population declines. Devil facial tumour 2 (DFT2) was identified in 2014, and evidence indicates that this new tumour has emerged independently of DFT1. While DFT1 is widespread across Tasmania, DFT2 is currently found only on the Channel Peninsula in south east Tasmania. Allograft transmission of cancer cells should be prevented by major histocompatibility complex (MHC) molecules. DFT1 avoids immune detection by downregulating MHC class I expression, which can be reversed by treatment with interferon-gamma (IFNγ), while DFT2 currently circulates in hosts with a similar MHC class I genotype to the tumour. Wild Tasmanian devil numbers have not recovered from the emergence of DFT1, and it is feared that widespread transmission of DFT2 will be devastating to the remaining wild population. A preventative solution for the management of the disease is needed. Here, we review the current research on immune responses to devil facial tumours and vaccine strategies against DFT1 and outline our plans moving forward to develop a specific, effective vaccine to support the wild Tasmanian devil population against the threat of these two transmissible tumours.

The newly-arisen Devil facial tumour disease 2 (DFT2) reveals a mechanism for the emergence of a contagious cancer.

Devil Facial Tumour 2 (DFT2) is a recently discovered contagious cancer circulating in the Tasmanian devil (Sarcophilus harrisii), a species which already harbours a more widespread contagious cancer, Devil Facial Tumour 1 (DFT1). Here we show that in contrast to DFT1, DFT2 cells express major histocompatibility complex (MHC) class I molecules, demonstrating that loss of MHC is not necessary for the emergence of a contagious cancer. However, the most highly expressed MHC class I alleles in DFT2 cells are common among host devils or non-polymorphic, reducing immunogenicity in a population sharing these alleles. In parallel, MHC class I loss is emerging in vivo, thus DFT2 may be mimicking the evolutionary trajectory of DFT1. Based on these results we propose that contagious cancers may exploit partial histocompatibility between the tumour and host, but that loss of allogeneic antigens could facilitate widespread transmission of DFT2.