Publications by authors named "Gregory M Woods"

59 Publications

NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers.

J Cancer Res Clin Oncol 2021 Jul 2;147(7):1973-1991. Epub 2021 Apr 2.

Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Private Bag 23, Hobart TAS 7000, Australia.

Purpose: Downregulation of MHC class I (MHC-I) is a common immune evasion strategy of many cancers. Similarly, two allogeneic clonal transmissible cancers have killed thousands of wild Tasmanian devils (Sarcophilus harrisii) and also modulate MHC-I expression to evade anti-cancer and allograft responses. IFNG treatment restores MHC-I expression on devil facial tumor (DFT) cells but is insufficient to control tumor growth. Transcriptional co-activator NLRC5 is a master regulator of MHC-I in humans and mice but its role in transmissible cancers remains unknown. In this study, we explored the regulation and role of MHC-I in these unique genetically mis-matched tumors.

Methods: We used transcriptome and flow cytometric analyses to determine how MHC-I shapes allogeneic and anti-tumor responses. Cell lines that overexpress NLRC5 to drive antigen presentation, and B2M-knockout cell lines incapable of presenting antigen on MHC-I were used to probe the role of MHC-I in rare cases of tumor regressions.

Results: Transcriptomic results suggest that NLRC5 plays a major role in MHC-I regulation in devils. NLRC5 was shown to drive the expression of many components of the antigen presentation pathway but did not upregulate PDL1. Serum from devils with tumor regressions showed strong binding to IFNG-treated and NLRC5 cell lines; antibody binding to IFNG-treated and NRLC5 transgenic tumor cells was diminished or absent following B2M knockout.

Conclusion: MHC-I could be identified as a target for anti-tumor and allogeneic immunity. Consequently, NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-021-03601-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017436PMC
July 2021

Mesenchymal plasticity of devil facial tumour cells during in vivo vaccine and immunotherapy trials.

Immunol Cell Biol 2021 08 21;99(7):711-723. Epub 2021 Mar 21.

School of Medicine, University of Tasmania, Hobart, TAS, Australia.

Immune evasion is critical to the growth and survival of cancer cells. This is especially pertinent to transmissible cancers, which evade immune detection across genetically diverse hosts. The Tasmanian devil (Sarcophilus harrisii) is threatened by the emergence of Devil Facial Tumour Disease (DFTD), comprising two transmissible cancers (DFT1 and DFT2). The development of effective prophylactic vaccines and therapies against DFTD has been restricted by an incomplete understanding of how allogeneic DFT1 and DFT2 cells maintain immune evasion upon activation of tumour-specific immune responses. In this study, we used RNA sequencing to examine tumours from three experimental DFT1 cases. Two devils received a vaccine prior to inoculation with live DFT1 cells, providing an opportunity to explore changes to DFT1 cancers under immune pressure. Analysis of DFT1 in the non-immunised devil revealed a 'myelinating Schwann cell' phenotype, reflecting both natural DFT1 cancers and the DFT1 cell line used for the experimental challenge. Comparatively, immunised devils exhibited a 'dedifferentiated mesenchymal' DFT1 phenotype. A third 'immune-enriched' phenotype, characterised by increased PDL1 and CTLA-4 expression, was detected in a DFT1 tumour that arose after immunotherapy. In response to immune pressure, mesenchymal plasticity and upregulation of immune checkpoint molecules are used by human cancers to evade immune responses. Similar mechanisms are associated with immune evasion by DFTD cancers, providing novel insights that will inform modification of DFTD vaccines. As DFT1 and DFT2 are clonal cancers transmitted across genetically distinct hosts, the Tasmanian devil provides a 'natural' disease model for more broadly exploring these immune evasion mechanisms in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.12451DOI Listing
August 2021

Tasmanian devil CD28 and CTLA4 capture CD80 and CD86 from adjacent cells.

Dev Comp Immunol 2021 02 8;115:103882. Epub 2020 Oct 8.

Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia. Electronic address:

Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumors. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily divergent species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dci.2020.103882DOI Listing
February 2021

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

Sci Adv 2020 Jul 1;6(27). Epub 2020 Jul 1.

Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS 7000, Australia.

Around 40% of humans and Tasmanian devils () develop cancer in their lifetime, compared to less than 10% for most species. In addition, devils are affected by two of the three known transmissible cancers in mammals. Immune checkpoint immunotherapy has transformed human medicine, but a lack of species-specific reagents has limited checkpoint immunology in most species. We developed a cut-and-paste reagent development system and used the fluorescent fusion protein system to show that immune checkpoint interactions are conserved across 160,000,000 years of evolution, CD200 is highly expressed on transmissible tumor cells, and coexpression of CD200R1 can block CD200 surface expression. The system's versatility across species was demonstrated by fusing a fluorescent reporter to a camelid-derived nanobody that binds human programmed death ligand 1. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can be used to advance our understanding of cancer and immunological tolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aba5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458443PMC
July 2020

A Devil of a Transmissible Cancer.

Trop Med Infect Dis 2020 Apr 1;5(2). Epub 2020 Apr 1.

Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS 7000, Australia.

Devil facial tumor disease (DFTD) encompasses two independent transmissible cancers that have killed the majority of Tasmanian devils. The cancer cells are derived from Schwann cells and are spread between devils during biting, a common behavior during the mating season. The Centers for Disease Control and Prevention (CDC) defines a parasite as "An organism that lives on or in a host organism and gets its food from, or at, the expense of its host." Most cancers, including DFTD, live within a host organism and derive resources from its host, and consequently have parasitic-like features. Devil facial tumor disease is a transmissible cancer and, therefore, DFTD shares one additional feature common to most parasites. Through direct contact between devils, DFTD has spread throughout the devil population. However, unlike many parasites, the DFTD cancer cells have a simple lifecycle and do not have either independent, vector-borne, or quiescent phases. To facilitate a description of devil facial tumor disease, this review uses life cycles of parasites as an analogy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/tropicalmed5020050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345153PMC
April 2020

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

Cell Mol Life Sci 2020 Jul 3;77(13):2507-2525. Epub 2020 Jan 3.

Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS, 7000, Australia.

The Tasmanian devil (Sarcophilus harrisii) is the only mammalian species known to be affected by multiple transmissible cancers. Devil facial tumours 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-019-03435-4DOI Listing
July 2020

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

Cell Mol Life Sci 2020 May 2;77(9):1847-1858. Epub 2019 Aug 2.

Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS, 7000, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-019-03259-2DOI Listing
May 2020

Editorial: Wild Immunology-The Answers Are Out There.

Front Immunol 2019 30;10:126. Epub 2019 Jan 30.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364755PMC
December 2019

Inducible IFN-γ Expression for MHC-I Upregulation in Devil Facial Tumor Cells.

Front Immunol 2018 14;9:3117. Epub 2019 Jan 14.

Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia.

The Tasmanian devil facial tumor (DFT) disease has led to an 80% reduction in the wild Tasmanian devil () population since 1996. The limited genetic diversity of wild devils and the lack of MHC-I expression on DFT cells have been implicated in the lack of immunity against the original DFT clonal cell line (DFT1). Recently, a second transmissible tumor of independent origin (DFT2) was discovered. Surprisingly, DFT2 cells do express MHC-I, but DFT2 cells appear to be on a trajectory for reduced MHC-I expression . Thus, much of the ongoing vaccine-development efforts and conservation plans have focused on MHC-I. A major limitation in conservation efforts is the lack of species-specific tools to understand Tasmanian devil gene function and immunology. To help fill this gap, we developed an all-in-one Tet-Off vector system to regulate expression of IFN-γ in DFT cells (DFT1.Tet/IFN-γ). IFN-γ can have negative effects on cell proliferation and viability; thus, doxycycline was used to suppress IFN-γ production whilst DFT1.Tet/IFN-γ cells were expanded in cell culture. Induction of IFN-γ following removal of doxycycline led to upregulation of MHC-I but also the inhibitory checkpoint molecule PD-L1. Additionally, DFT1.Tet/IFN-γ cells were capable of stimulating MHC-I upregulation on bystander wild type DFT cells in co-culture assays . This system represents a major step forward in DFT disease immunotherapy and vaccine development efforts, and ability to understand gene function in devils. Importantly, the techniques are readily transferable for testing gene function in DFT2 cells and other non-traditional species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.03117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340284PMC
October 2019

TNF May Negatively Regulate Phagocytosis of Devil Facial Tumour Disease Cells by Activated Macrophages.

Immunol Invest 2019 Oct 19;48(7):691-703. Epub 2019 Jan 19.

Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania , Hobart , Tasmania , Australia.

: Macrophage phagocytosis of pathogens and tumour cells is an important early event in protection against infectious disease and cancer. As tumour necrosis factor α (TNF) is an important cytokine in macrophage activation, we investigated the involvement of TNF in macrophage phagocytosis of tumour cells. : We used Devil Facial Tumour Disease (DFTD) cancer cells as the target tumour cells. The Tasmanian devil (Sarcophilus harrisii) population is threatened by the transmissible DFTD. Using DFTD cells provided the opportunity to determine if these cells can be phagocytosed and investigate requirement for TNF. As effector cells, bone marrow derived macrophages (BMDMs), generated from C57BL/6 wild type (B6.WT) and C57BL/6 TNF-/- (B6.TNF-/-) mice were used. Phagocytosis of DFTD cells was investigated by confocal microscopy and flow cytometry. : DFTD cells were consistently phagocytosed by B6.WT and B6.TNF-/- BMDMs with similar efficiency in vitro. Consequently the DFTD cells are not resistant to phagocytosis. Following activation by exposure to IFNγ and LPS or LPS alone, B6.TNF-/- BMDMs had higher phagocytic efficiency and lower nitric oxide (NO) production compared to wild-type controls. In addition, NO seems to be unlikely to be the involved in phagocytosis efficiency in IFNγ and LPS activated B6.TNF-/- macrophages and consequences thereof. : Our results indicate that TNF is not required for IFNγ and LPS or LPS alone activation of macrophage phagocytosis. TNF may negatively regulate macrophage phagocytosis of tumour cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08820139.2018.1515222DOI Listing
October 2019

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Cancer Cell 2019 01;35(1):125-139.e9

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335503PMC
January 2019

Two Decades of the Impact of Tasmanian Devil Facial Tumor Disease.

Integr Comp Biol 2018 12;58(6):1043-1054

School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7005, Australia.

The Tasmanian devil, a marsupial carnivore, has been restricted to the island state of Tasmania since its extinction on the Australian mainland about 3000 years ago. In the past two decades, this species has experienced severe population decline due to the emergence of devil facial tumor disease (DFTD), a transmissible cancer. During these 20 years, scientists have puzzled over the immunological and evolutionary responses by the Tasmanian devil to this transmissible cancer. Targeted strategies in population management and disease control have been developed as well as comparative processes to identify variation in tumor and host genetics. A multi-disciplinary approach with multi-institutional teams has produced considerable advances over the last decade. This has led to a greater understanding of the molecular pathogenesis and genomic classification of this cancer. New and promising developments in the Tasmanian devil's story include evidence that most immunized, and some wild devils, can produce an immune response to DFTD. Furthermore, epidemiology combined with genomic studies suggest a rapid evolution to the disease and that DFTD will become an endemic disease. Since 1998 there have been more than 350 publications, distributed over 37 Web of Science categories. A unique endemic island species has become an international curiosity that is in the spotlight of integrative and comparative biology research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/icb/icy118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927850PMC
December 2018

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

Elife 2018 08 14;7. Epub 2018 Aug 14.

Department of Biological Sciences, University of Southampton, Southampton, United Kingdom.

Devil Facial Tumour 2 (DFT2) is a recently discovered contagious cancer circulating in the Tasmanian devil (), 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.35314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092122PMC
August 2018

Heat shock proteins expressed in the marsupial Tasmanian devil are potential antigenic candidates in a vaccine against devil facial tumour disease.

PLoS One 2018 27;13(4):e0196469. Epub 2018 Apr 27.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

The Tasmanian devil (Sarcophilus harrisii), the largest extant carnivorous marsupial and endemic to Tasmania, is at the verge of extinction due to the emergence of a transmissible cancer known as devil facial tumour disease (DFTD). DFTD has spread over the distribution range of the species and has been responsible for a severe decline in the global devil population. To protect the Tasmanian devil from extinction in the wild, our group has focused on the development of a prophylactic vaccine. Although this work has shown that vaccine preparations using whole DFTD tumour cells supplemented with adjuvants can induce anti-DFTD immune responses, alternative strategies that induce stronger and more specific immune responses are required. In humans, heat shock proteins (HSPs) derived from tumour cells have been used instead of whole-tumour cell preparations as a source of antigens for cancer immunotherapy. As HSPs have not been studied in the Tasmanian devil, this study presents the first characterisation of HSPs in this marsupial and evaluates the suitability of these proteins as antigenic components for the enhancement of a DFTD vaccine. We show that tissues and cancer cells from the Tasmanian devil express constitutive and inducible HSP. Additionally, this study suggests that HSP derived from DFTD cancer cells are immunogenic supporting the future development of a HSP-based vaccine against DFTD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196469PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922574PMC
July 2018

Transcriptome and proteome profiling reveals stress-induced expression signatures of imiquimod-treated Tasmanian devil facial tumor disease (DFTD) cells.

Oncotarget 2018 Mar 23;9(22):15895-15914. Epub 2018 Mar 23.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.

As a topical cancer immunotherapy, the toll-like receptor 7 ligand imiquimod activates tumor regression via stimulation of immune cell infiltration and cytotoxic responses. Imiquimod also exerts direct pro-apoptotic effects on tumor cells , but a role for these effects in imiquimod-induced tumor regression remains undefined. We previously demonstrated that cell lines derived from devil facial tumor disease (DFTD), a transmissible cancer threatening the survival of the Tasmanian devil (), are sensitive to imiquimod-induced apoptosis. In this study, the pro-apoptotic effects of imiquimod in DFTD have been investigated using RNA-sequencing and label-free quantitative proteomics. This analysis revealed that changes to gene and protein expression in imiquimod treated DFTD cells are consistent with the onset of oxidative and endoplasmic reticulum stress responses, and subsequent activation of the unfolded protein response, autophagy, cell cycle arrest and apoptosis. Imiquimod also regulates the expression of oncogenic pathways, providing a direct mechanism by which this drug may increase tumor susceptibility to immune cytotoxicity . Our study has provided the first global analysis of imiquimod-induced effects in any tumor cell line. These findings have highlighted the potential of cell stress pathways as therapeutic targets in DFTD, and will allow for improved mechanistic use of imiquimod as a therapy in both the Tasmanian devil and human cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882306PMC
March 2018

The Origins and Vulnerabilities of Two Transmissible Cancers in Tasmanian Devils.

Cancer Cell 2018 04;33(4):607-619.e15

Transmissible Cancer Group, Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. Electronic address:

Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. Although rare in nature, two facial tumor clones affect Tasmanian devils. Here we perform comparative genetic and functional characterization of these lineages. The two cancers have similar patterns of mutation and show no evidence of exposure to exogenous mutagens or viruses. Genes encoding PDGF receptors have copy number gains and are present on extrachromosomal double minutes. Drug screening indicates causative roles for receptor tyrosine kinases and sensitivity to inhibitors of DNA repair. Y chromosome loss from a male clone infecting a female host suggests immunoediting. These results imply that Tasmanian devils may have inherent susceptibility to transmissible cancers and present a suite of therapeutic compounds for use in conservation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2018.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896245PMC
April 2018

Maternal exposure to particulate matter alters early post-natal lung function and immune cell development.

Environ Res 2018 07 5;164:625-635. Epub 2018 Apr 5.

School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia. Electronic address:

Background: In utero exposure to particulate matter (PM) from a range of sources is associated with adverse post-natal health; however, the effect of maternal exposure to community-sampled PM on early post-natal lung and immune development is poorly understood.

Objectives: Using a mouse model, we aimed to determine whether in utero exposure to PM alters early post-natal lung function and immune cell populations. We used PM collected from ceiling voids in suburban houses as a proxy for community PM exposure.

Methods: Pregnant C57BL/6 mice were intranasally exposed to ceiling derived PM, or saline alone, at gestational day (E) 13.5, 15.5, and 17.5. When mice were two weeks old, we assessed lung function by the forced oscillation technique, and enumerated T and B cell populations in the spleen and thymus by flow cytometry.

Results: Maternal exposure to PM impaired somatic growth of male offspring resulting in reduced lung volume and deficits in lung function. There was no effect on thymic T cell populations in dams and their male offspring but PM decreased the CD4 +CD25 + T cell population in the female offspring. In contrast, maternal exposure to PM increased splenic CD3 +CD4 + and CD3 +CD8 + T cells in dams, and there was some evidence to suggest inhibition of splenic T cell maturation in male but not female offspring.

Conclusions: Our findings suggested that maternal exposure to ceiling void PM has the capacity to impair early somatic growth and alter early life immune development in a sex specific manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2018.03.029DOI Listing
July 2018

Gomesin peptides prevent proliferation and lead to the cell death of devil facial tumour disease cells.

Cell Death Discov 2018 Dec 14;4:19. Epub 2018 Feb 14.

1QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006 Australia.

The Tasmanian devil faces extinction due to devil facial tumour disease (DFTD), a highly transmittable clonal form of cancer without available treatment. In this study, we report the cell-autonomous antiproliferative and cytotoxic activities exhibited by the spider peptide gomesin (AgGom) and gomesin-like homologue (HiGom) in DFTD cells. Mechanistically, both peptides caused a significant reduction at G0/G1 phase, in correlation with an augmented expression of the cell cycle inhibitory proteins p53, p27, p21, necrosis, exacerbated generation of reactive oxygen species and diminished mitochondrial membrane potential, all hallmarks of cellular stress. The screening of a novel panel of AgGom-analogues revealed that, unlike changes in the hydrophobicity and electrostatic surface, the cytotoxic potential of the gomesin analogues in DFTD cells lies on specific arginine substitutions in the eight and nine positions and alanine replacement in three, five and 12 positions. In conclusion, the evidence supports gomesin as a potential antiproliferative compound against DFTD disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41420-018-0030-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841354PMC
December 2018

Immunization Strategies Producing a Humoral IgG Immune Response against Devil Facial Tumor Disease in the Majority of Tasmanian Devils Destined for Wild Release.

Front Immunol 2018 19;9:259. Epub 2018 Feb 19.

School of Medicine, University of Tasmania, Hobart, TAS, Australia.

Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government's Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials ( = 19 and  = 33), these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIX™, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIX™, polyICLC (Hiltonol) and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of devils in these anti-DFTD immunization trials was remarkable, especially as DFTD is hallmarked by its immune evasion mechanisms. Microsatellite analyzes of MHC revealed that some MHC-I microsatellites correlated to stronger immune responses. These trials signify the first step in the long-term objective of releasing devils with immunity to DFTD into the wild.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826075PMC
April 2019

The toll-like receptor ligands Hiltonol (polyICLC) and imiquimod effectively activate antigen-specific immune responses in Tasmanian devils (Sarcophilus harrisii).

Dev Comp Immunol 2017 11 6;76:352-360. Epub 2017 Jul 6.

Menzies Institute for Medical Research, University of Tasmania, Hobart 7000, Tasmania, Australia; School of Medicine, University of Tasmania, Hobart 7000, Tasmania, Australia.

Devil facial tumour disease (DFTD) describes two genetically distinct transmissible tumours that pose a significant threat to the survival of the Tasmanian devil. A prophylactic vaccine could protect devils from DFTD transmission. For this vaccine to be effective, potent immune adjuvants will be required. Toll-like receptors (TLRs) promote robust immune responses in human cancer studies and are highly conserved across mammalian species. In this study, we investigated the proficiency of TLR ligands for immune activation in the Tasmanian devil using in vitro mononuclear cell stimulations and in vivo immunisation trials with a model antigen. We identified two such TLR ligands, polyICLC (Hiltonol) (TLR3) and imiquimod (TLR7), that in combination induced significant IFNγ production from Tasmanian devil lymphocytes in vitro. Immunisation with these ligands and the model antigen keyhole limpet haemocyanin activated robust antigen-specific primary, secondary and long-term memory IgG responses. Our results support the conserved nature of TLR signaling across mammalian species. PolyICLC and imiquimod will be trialed as immune adjuvants in future DFTD vaccine formulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dci.2017.07.004DOI Listing
November 2017

The absence of TNF permits myeloid Arginase 1 expression in experimental L. monocytogenes infection.

Immunobiology 2017 08 16;222(8-9):913-917. Epub 2017 May 16.

Menzies Institute for Medical Research Tasmania, MS2, 17 Liverpool St, Hobart 7000, Tasmania, Australia; Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Engineering Technology Research Center of Anti-inflammatory and Immunodrugs, Hefei, Anhui, China. Electronic address:

During an immune response inflammatory macrophages with their wide variety of effector mechanisms including the expression of inducible nitric oxide synthase play an important part in the defense against invading pathogens. The inflammatory phenotype requires the presence of TNF which suppresses alternative activation. In the bacterial Listeria monocytogenes infection model inflammatory macrophages are crucial for protection. After infection, TNF-deficient hosts have a similar number of splenic macrophages but die rapidly. A more detailed analysis of these cells showed that while inducible nitric oxide synthase is expressed at a comparable level TNF-deficient macrophages show an increased expression of Arginase 1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imbio.2017.05.012DOI Listing
August 2017

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease.

Front Immunol 2017 3;8:513. Epub 2017 May 3.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil () facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.00513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413580PMC
May 2017

Regression of devil facial tumour disease following immunotherapy in immunised Tasmanian devils.

Sci Rep 2017 03 9;7:43827. Epub 2017 Mar 9.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.

Devil facial tumour disease (DFTD) is a transmissible cancer devastating the Tasmanian devil (Sarcophilus harrisii) population. The cancer cell is the 'infectious' agent transmitted as an allograft by biting. Animals usually die within a few months with no evidence of antibody or immune cell responses against the DFTD allograft. This lack of anti-tumour immunity is attributed to an absence of cell surface major histocompatibility complex (MHC)-I molecule expression. While the endangerment of the devil population precludes experimentation on large experimental groups, those examined in our study indicated that immunisation and immunotherapy with DFTD cells expressing surface MHC-I corresponded with effective anti-tumour responses. Tumour engraftment did not occur in one of the five immunised Tasmanian devils, and regression followed therapy of experimentally induced DFTD tumours in three Tasmanian devils. Regression correlated with immune cell infiltration and antibody responses against DFTD cells. These data support the concept that immunisation of devils with DFTD cancer cells can successfully induce humoral responses against DFTD and trigger immune-mediated regression of established tumours. Our findings support the feasibility of a protective DFTD vaccine and ultimately the preservation of the species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep43827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343465PMC
March 2017

Demonstration of immune responses against devil facial tumour disease in wild Tasmanian devils.

Biol Lett 2016 Oct;12(10)

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia

Devil facial tumour disease (DFTD) is a recently emerged fatal transmissible cancer decimating the wild population of Tasmanian devils (Sarcophilus harrisii). Biting transmits the cancer cells and the tumour develops in the new host as an allograft. The literature reports that immune escape mechanisms employed by DFTD inevitably result in host death. Here we present the first evidence that DFTD regression can occur and that wild devils can mount an immune response against the disease. Of the 52 devils tested, six had serum antibodies against DFTD cells and, in one case, prominent T lymphocyte infiltration in its tumour. Notably, four of the six devils with serum antibody had histories of DFTD regression. The novel demonstration of an immune response against DFTD in wild Tasmanian devils suggests that a proportion of wild devils can produce a protective immune response against naturally acquired DFTD. This has implications for tumour-host coevolution and vaccine development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsbl.2016.0553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095191PMC
October 2016

PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-γ and Can Be Expressed in the Tumor Microenvironment.

Front Immunol 2016 9;7:581. Epub 2016 Dec 9.

Experimental Therapeutics Laboratory, Hanson Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia; Experimental Therapeutics Laboratory, Sansom Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia; Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.

The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil () population. The first transmissible tumor, now termed devil facial tumor 1 (DFT1), was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015, a second transmissible cancer [devil facial tumor 2 (DFT2)] was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promotes antitumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade antitumor immune responses. We developed recombinant proteins and monoclonal antibodies (mAbs) to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-γ. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1 non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, testing suggests that PD-1 binding to PD-L1 and PD-L2 can be blocked by mAbs, which could be critical to understanding how the DFT allografts evade the immune system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2016.00581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145852PMC
December 2016

The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines.

PLoS One 2016 9;11(12):e0168068. Epub 2016 Dec 9.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

The survival of the Tasmanian devil (Sarcophilus harrisii) is threatened by devil facial tumour disease (DFTD). This transmissible cancer is usually fatal, and no successful treatments have been developed. In human studies, the small immunomodulatory molecule imiquimod is a successful immunotherapy, activating anti-tumour immunity via stimulation of toll-like receptor-7 (TLR7) signaling pathways. In addition, imiquimod is a potent inducer of apoptosis in human tumour cell lines via TLR7 independent mechanisms. Here we investigate the potential of imiquimod as a DFTD therapy through analysis of treated DFTD cell lines and Tasmanian devil fibroblasts. WST-8 proliferation assays and annexin V apoptosis assays were performed to monitor apoptosis, and changes to the expression of pro- and anti-apoptotic genes were analysed using qRT-PCR. Our results show that DFTD cell lines, but not Tasmanian devil fibroblasts, are sensitive to imiquimod-induced apoptosis in a time and concentration dependent manner. Induction of apoptosis was accompanied by down-regulation of the anti-apoptotic BCL2 and BCLXL genes, and up-regulation of the pro-apoptotic BIM gene. Continuous imiquimod treatment was required for these effects to occur. These results demonstrate that imiquimod can deregulate DFTD cell growth and survival in direct and targeted manner. In vivo, this may increase DFTD vulnerability to imiquimod-induced TLR7-mediated immune responses. Our findings have improved the current knowledge of imiquimod action in tumour cells for application to both DFTD and human cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148113PMC
July 2017

Discovery of Biomarkers for Tasmanian Devil Cancer (DFTD) by Metabolic Profiling of Serum.

J Proteome Res 2016 10 23;15(10):3827-3840. Epub 2016 Sep 23.

Australian Centre for Research on Separation Science (ACROSS), School of Physical Sciences, University of Tasmania , Private Bag 75, Hobart, Tasmania 7001, Australia.

Devil facial tumor disease (DFTD) is a transmissible cancer threatening Tasmanian devils (Sarcophilus harrisii) with extinction. There is no preclinical test available for DFTD, and thus our aim was to find biomarkers for DFTD by metabolic fingerprinting. Seventy serum samples from wild Tasmanian devils (35 controls, 35 with tumors) were analyzed by liquid chromatography-high-resolution mass spectrometry. Features were selected by multivariate models (PLS/DA, random forests) comparing age-matched training set (n = 20 × 2) and further complying with fold-change threshold (≥1.4) and Mann-Whitney U-tests with correction for multiple hypotheses (false discovery rate (FDR) q < 0.05). An array of overlapping peptide segments of the N-terminal end of fibrinogen were the strongest positive DFTD markers. These peptides recorded fold-change up to 90, FDR-corrected p value below 0.01, and area under ROC curve of at least 0.80 and also correlated with tumor size (Spearman R > 0.45, p < 0.01). Additional potential markers included amino acid and lipid metabolites, while cortisol and urea were the most significant health predictors (AUC ≥ 0.90). PLS/DA resulted in AUC = 0.997 for the training set and overall sensitivity of 91% and specificity of 97%. A support vector machine model utilizing only the major peptide marker and seven other metabolites led to overall 94% sensitivity and specificity. The novel findings in this first DFTD metabolomics study shed light on metabolic changes in Tasmanian devils affected by DFTD and provide a valuable step toward the development of prognostic biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.6b00629DOI Listing
October 2016

Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo.

Oncotarget 2016 Jul;7(29):46028-46041

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.

The morbidity and mortality associated with current therapies for acute promyelocytic leukemia (APL) remain a significant clinical concern, despite improvements in patient survival. Consequently, the development of adjuvant therapies that increase efficacy while reducing morbidities is important. Reducing the concentration of the toxic drugs in adjuvant therapy has the potential to reduce unwanted side effects. Therefore, this study aimed to determine the synergistic effects of fucoidan, an anti-tumor agent, with current APL therapies.When the human APL cell line, NB4, was treated in vitro with fucoidan plus ATO and ATRA at therapeutic and sub-therapeutic doses, there was an increase in sub-G0/G1 cells, annexin V/PI-positive-apoptotic cells and DNA fragmentation. This reduction in proliferation and increase in apoptosis was accompanied by enhanced myeloid differentiation as indicated by an increased expression of CD11b. This was not observed with the AML cell line Kasumi-1, suggesting specificity for APL.In vivo treatment of APL-bearing mice with fucoidan+ATRA or fucoidan+ATO delayed tumor growth, induced differentiation and increased tumor volume doubling time. The differentiated APL cells derived from the excised tumor mass exhibited decreased CD44 expression in fucoidan+ATRA treated mice. This could translate to decreased cell migration in APL patients.Our findings provide evidence supporting the use of fucoidan as an adjuvant therapeutic agent in the treatment of APL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.10016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216779PMC
July 2016

Mitogen-activated Tasmanian devil blood mononuclear cells kill devil facial tumour disease cells.

Immunol Cell Biol 2016 08 19;94(7):673-9. Epub 2016 Apr 19.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Devil facial tumour disease (DFTD) is a transmissible cancer that has brought the host species, the Tasmanian devil, to the brink of extinction. The cancer cells avoid allogeneic immune recognition by downregulating cell surface major histocompatibility complex (MHC) I expression. This should prevent CD8(+) T cell, but not natural killer (NK) cell, cytotoxicity. The reason why NK cells, normally reactive to MHC-negative cells, are not activated to kill DFTD cells has not been determined. The immune response of wild devils to DFTD, if it occurs, is uncharacterised. To investigate this, we tested 12 wild devils with DFTD, and found suggestive evidence of low levels of antibodies against DFTD cells in one devil. Eight of these devils were also analysed for cytotoxicity, however, none showed evidence for cytotoxicity against cultured DFTD cells. To establish whether mimicking activation of antitumour responses could induce cytotoxic activity against DFTD, Tasmanian devil peripheral blood mononuclear cells (PBMCs) were treated with either the mitogen Concanavalin A, the Toll-like receptor agonist polyinosinic:polycytidylic acid or recombinant Tasmanian devil IL-2. All induced the PBMC cells to kill cultured DFTD cells, suggesting that activation does not occur after encounter with DFTD cells in vivo, but can be induced. The identification of agents that activate cytotoxicity against DFTD target cells is critical for developing strategies to protect against DFTD. Such agents could function as adjuvants to induce functional immune responses capable of targeting DFTD cells and tumours in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/icb.2016.38DOI Listing
August 2016

A second transmissible cancer in Tasmanian devils.

Proc Natl Acad Sci U S A 2016 Jan 28;113(2):374-9. Epub 2015 Dec 28.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia;

Clonally transmissible cancers are somatic cell lineages that are spread between individuals via the transfer of living cancer cells. There are only three known naturally occurring transmissible cancers, and these affect dogs, soft-shell clams, and Tasmanian devils, respectively. The Tasmanian devil transmissible facial cancer was first observed in 1996, and is threatening its host species with extinction. Until now, this disease has been consistently associated with a single aneuploid cancer cell lineage that we refer to as DFT1. Here we describe a second transmissible cancer, DFT2, in five devils located in southern Tasmania in 2014 and 2015. DFT2 causes facial tumors that are grossly indistinguishable but histologically distinct from those caused by DFT1. DFT2 bears no detectable cytogenetic similarity to DFT1 and carries a Y chromosome, which contrasts with the female origin of DFT1. DFT2 shows different alleles to both its hosts and DFT1 at microsatellite, structural variant, and major histocompatibility complex (MHC) loci, confirming that it is a second cancer that can be transmitted between devils as an allogeneic, MHC-discordant graft. These findings indicate that Tasmanian devils have spawned at least two distinct transmissible cancer lineages and suggest that transmissible cancers may arise more frequently in nature than previously considered. The discovery of DFT2 presents important challenges for the conservation of Tasmanian devils and raises the possibility that this species is particularly prone to the emergence of transmissible cancers. More generally, our findings highlight the potential for cancer cells to depart from their hosts and become dangerous transmissible pathogens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1519691113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720317PMC
January 2016
-->