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

Abstract

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.

Class II transactivator induces expression of MHC-I and MHC-II in transmissible Tasmanian devil facial tumours

“…12: 220208 low CIITA-expressing cells. Alternatively, the inability to express MHC-II molecules in CIITA-overexpressing DFT2 cells might be due to epigenetic or post-transcriptional regulation, possibly as a consequence of the differentiation state of DFT2 tumours compared to DFT1 [29,57]. A heterozygous non-synonymous mutation (D59N) in transcription factor RFX5 was also described in DFT2 tumours [6].…”

“…The lower expression of CIITA in CIITA-transfected DFT2 cells compared to CIITA-transfected DFT1 cells could be due to factors related to transgene copy number, genomic stability and integration sites, cellular metabolic state, or selection of low CIITA-expressing cells. Alternatively, the inability to express MHC-II molecules in CIITA-overexpressing DFT2 cells might be due to epigenetic or post-transcriptional regulation, possibly as a consequence of the differentiation state of DFT2 tumours compared to DFT1 [ 29 , 57 ]. A heterozygous non-synonymous mutation (D59N) in transcription factor RFX5 was also described in DFT2 tumours [ 6 ].…”

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

“…The cellular origins of DFT1 and DFT2 could explain their different competitive capacities. DFT1 originated from a well‐differentiated myelinating Schwann cell (Owen et al., 2021 ) a cell type that usually exits the cell cycle and ceases growth (Tikoo et al., 2000 ; Yamauchi et al., 2004 ); however, DFT2 originated from a less differentiated immature or repair Schwann cell (Owen et al., 2021 ; Patchett et al., 2019 ), a cell type that retains the ability to proliferate (Tikoo et al., 2000 ; Yamauchi et al., 2004 ). Previous work (Patchett et al., 2019 ) found that, in comparison with DFT1, DFT2 transcriptomes were enriched in genes linked to cell migration consistent with a repair Schwann cell origin.…”

“…Visual examination of the DFT1 and DFT2 cells revealed morphological differences: DFT2 cells have a neuron-like phenotype, similar to their Schwann cell progenitor (Owen et al, 2021), while DFT1 cells have a rounder shape (Figure 1b,c). To test the hypothesis that DFT2 is a better competitor than DFT1, we first grew DFT1 and DFT2 cell lines in monoculture (Figure 2).…”