Spontaneous Tumor Regression in Tasmanian Devils Associated with RASL11A Activation

Abstract

Spontaneous tumor regression has been documented in a small proportion of human cancer patients, but the specific mechanisms underlying tumor regression without treatment are not well-understood. Tasmanian devils are threatened with extinction from a transmissible cancer due to universal susceptibility and a near 100% case fatality rate. In over 10,000 cases, fewer than 20 instances of natural tumor regression have been detected. Previous work in this system has focused on Tasmanian devil genetic variation associated with the regression phenotype. Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5' untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression. RASL11A was expressed in regressed tumors but silenced in wild-type, non-regressed tumors, consistent with RASL11A down-regulation in human cancers. Induced RASL11A expression significantly reduced tumor cell proliferation in vitro. The RAS pathway is frequently altered in human cancers, and RASL11A activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.

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

“…However, we also found support for overlapping contemporary and historical selection on some gene networks. Our work contributes to mounting evidence identifying possible mechanisms by which devil populations are persisting and rapidly evolving in the face of DFTD despite overall low genetic diversity and population bottlenecks (2,25,50,69,70). Broadly, this type of approach can be applied to selection analyses of novel threats in wildlife populations in the current era of anthropogenic global change and guide monitoring and management actions focused on genetic adaptive potential.…”

Darwin, the devil, and the management of transmissible cancers

“…Devils from populations in northwestern Tasmania mounted immune responses to DFTD, concomitant with natural tumor regressions and recovery after infection (Pye et al 2016a) (Fig 1). Devils with regressed tumors differed genetically from those with nonregressed tumors (Margres et al 2018a), and tumor regressions appear to be affected by upregulation of putative tumor suppressor RASL11a, a gene not expressed in human cancers (Margres et al 2020). Allele frequencies in genomic regions associated with immune function and cancer changed significantly 4-6 generations after disease arrival (Epstein et al 2016).…”

“…2018 a ), and tumor regressions appear to be affected by upregulation of putative tumor suppressor RASL11a, a gene not expressed in human cancers (Margres et al. 2020). Allele frequencies in genomic regions associated with immune function and cancer changed significantly 4‐6 generations after disease arrival (Epstein et al.…”

Gene expression of Tasmanian devil facial tumors differs among host populations

“…Although putative functions of candidate genes identi ed in these studies suggest biological functions that may underlie variation in host tness, mechanistic differences in response to infection between sexes remain unclear. Additionally, isolated cases of spontaneous tumor regression have been observed in the eld, the molecular underpinnings of which appear to be in regulatory regions because no non-synonymous substitutions have been found in either the devils or tumors [37,38]. Further, phenotypic responses in devil populations following DFTD arrival have been observed within one or two generations [33], suggesting existing plasticity and not a purely adaptive response.…”

“…Studies comparing transcriptomic and genomic variation are ideally suited for elucidating the molecular basis for variation in devil responses to DFTD. However, previous gene expression studies of DFTD have aimed to identify cell type of origin [22] or targeted speci c sets of immune-related genes, primarily in laboratory-cultured DFTD cell lines [e.g., [38][39][40][41]. Thus, there is a need to understand variation in both host and DFTD tumor gene expression in natural populations, particularly with respect to observed variation in DFTD-associated impacts on hosts.…”