Two of a kind: transmissible Schwann cell cancers in the endangered Tasmanian devil (Sarcophilus harrisii)

Abstract

Devil facial tumour disease (DFTD) comprises two genetically distinct transmissible cancers (DFT1 and DFT2) endangering the survival of the Tasmanian devil (Sarcophilus harrisii) in the wild. DFT1 first arose from a cell of the Schwann cell lineage; however, the tissue-of-origin of the recently discovered DFT2 cancer is unknown. In this study, we compared the transcriptome and proteome of DFT2 tumours to DFT1 and normal Tasmanian devil tissues to determine the tissue-of-origin of the DFT2 cancer. Our findings demonstrate that DFT2 expresses a range of Schwann cell markers and exhibits expression patterns consistent with a similar origin to the DFT1 cancer. Furthermore, DFT2 cells express genes associated with the repair response to peripheral nerve damage. These findings suggest that devils may be predisposed to transmissible cancers of Schwann cell origin. The combined effect of factors such as frequent nerve damage from biting, Schwann cell plasticity and low genetic diversity may allow these cancers to develop on rare occasions. The emergence of two independent transmissible cancers from the same tissue in the Tasmanian devil presents an unprecedented opportunity to gain insight into cancer development, evolution and immune evasion in mammalian species.

A novel system to map protein interactions reveals evolutionarily conserved immune evasion pathways on transmissible cancers

“…In addition to high expression of CD200 on neuroendocrine neoplasms 40, 44 , CD200 is used as a diagnostic marker for several human blood cancers 45–47 . DFT cells metastasize in the majority of cases 48 and our transcriptome results (Figure 5A) suggest that CD200 mRNA is more highly expressed in DFT cells than in peripheral blood mononuclear cells (PBMCs) 34, 35 . As a result, we tested if CD200 could be used to identify DFT cells in blood.…”

“…Analysis of previously published devil and DFT cell transcriptomes suggested that CD200 mRNA is highly expressed in DFT2 cells and peripheral nerves, moderately expressed in DFT1 cells, and lower in other healthy devil tissues (Figure 5A) 34, 35, 39 . As CD200 is an inhibitory molecule expressed on most human neuroendocrine neoplasms 40 , and both DFT1 and DFT2 originated from Schwann cells 35, 41 , we sought to investigate CD200 expression on DFT cells at the protein level. Staining of wild-type DFT1 and DFT2 cells with CD200R1-mOrange FAST protein showed minimal fluorescent signal (Figure 5B).…”

“…We chose additional immune checkpoint molecules for FAST protein development (Figure 3A) based on targets of clinical trials and sequence analysis of devil genes 27, 34, 35 . We transfected the FAST protein expression vectors ( Table S2 ) into CHO cells and tested the supernatant against CHO cell lines expressing full-length receptors.…”

“…RNAseq data was generated during previous experiments, aligned against the reference Tasmanian devil genome Devil_ref v7.0 (GCA_000189315.1) and summarised into normalized read counts as previously described 34, 35 . RPKM-normalized read counts were produced in R using edgeR 82 .…”

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

“…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…”