Curse of the devil: molecular insights into the emergence of transmissible cancers in the Tasmanian devil (Sarcophilus harrisii)

Abstract

The Tasmanian devil ( Sarcophilus harrisii ) is the only mammalian species known to be affected by multiple transmissible cancers. Devil facial tumour 1 and 2 (DFT1 and DFT2) are independent neoplastic cell lineages that produce large, disfiguring cancers known as devil facial tumour disease (DFTD). The long-term persistence of wild Tasmanian devils is threatened due to the ability of DFTD cells to propagate as contagious allografts and the high mortality rate of DFTD. Recent studies have demonstrated that both DFT1 and DFT2 cancers originated from founder cells of the Schwann cell lineage, an uncommon origin of malignant cancer in humans. This unprecedented finding has revealed a potential predisposition of Tasmanian devils to transmissible cancers of the Schwann cell lineage. In this review, we compare the molecular nature of human Schwann cells and nerve sheath tumours with DFT1 and DFT2 to gain insights into the emergence of transmissible cancers in the Tasmanian devil. We discuss a potential mechanism whereby Schwann cell plasticity and frequent wounding in Tasmanian devils combine with an inherent cancer predisposition and low genetic diversity to give rise to transmissible Schwann cell cancers in devils on rare occasions. Response to Reviewers:We appreciate the suggestions and have incorporated all into the revised version. Thank you.

Passage of transmissible cancers in the Tasmanian devil is due to a dominant, shared peptide motif and a limited repertoire of MHC-I allotypes

“…We have identified four unique 8/9mer peptide sequences deriving from four source proteins which are present on the surface of both DFT1+IFNg and DFT2, but not fibroblast cells. These peptides derived from source proteins which are specific to or overexpressed in cells of the nervous system (including Schwann cell development), which supports previous studies proposing a common cellular origin for the tumours (29). Further analysis is needed to characterise the peptide repertoires of more tissues in the Tasmanian devil and to identify mutated peptide antigens, but the identification of unique peptides in DFT1+IFNg and DFT2 from proteins with differential tissue expression indicates that tumour associated or tumour specific antigens may exist in both DFT1 and DFT2.…”

“…As reported previously for other species (17,(24)(25)(26), the use of small amino acids increased whereas the frequency of bulky amino acids decreased with increasing peptide length in devil (supplementary table 6). As DFT1+IFNg and DFT2 are are predicted to have the same cellular origin, a Schwann cell (27)(28)(29), we identififed the peptides that derive from source proteins with a neural function that…”

Contemporary and historical selection in Tasmanian devils (Sarcophilus harrisii) support novel, polygenic response to transmissible cancer

“…Our GO enrichment result for middle ear development (GO:0042474) among contemporary candidates may highlight selection for interactions with the peripheral nervous system and cell proliferation. Genes annotated with nervous system associations may indicate selection for behavioural changes (28), or highlight importance and vulnerability of peripheral nerve repair by Schwann cells in devils, given the prevalence of biting and Schwann cell origin of DFT (41). Significant overlap for genes associated with devil infection status (case-control), age, and survival (47) among our contemporary candidates is a strong indicator that these contemporary candidates likely confer relevant phenotypic change.…”

“…Our GO enrichment result for middle ear development (GO:0042474) among contemporary candidates may highlight selection for interactions with the peripheral nervous system and cell proliferation. Whereas Hubert and colleagues (47) suggested genes with nervous system annotations may be indicative of selection for behavioural changes, others have pointed out the importance and vulnerability of peripheral nerve repair by Schwann cells in devils, given the prevalence of biting and Schwann cell origin of DFT (40). Regardless, genes and their products at the interface of the nervous system and proliferation could prove to be important candidates.…”

“…Comparative and functional analyses of DFTD and DFT2 showed similar drivers of cancerous mutations and tissue type of origin (37). Low genetic diversity, chromosomal fragility (38), a reportedly high incidence of non-transmissible neoplasms (39), and injury-prone biting behaviour (40) may contribute to a predisposition to transmissible cancers in devils (41). These findings suggest that transmissible cancers may be a recurring selective force in the Tasmanian devil lineage.…”