ORCID Profile
0000-0002-8424-4680
Current Organisations
CSIRO
,
CSIRO Oceans and Atmosphere
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Publisher: Wiley
Date: 08-2016
Publisher: Informa UK Limited
Date: 02-01-2020
Publisher: Frontiers Media SA
Date: 19-02-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-07-2020
Abstract: A simple cut-and-paste reagent development method applicable to any species reveals checkpoint molecules on transmissible cancers.
Publisher: Springer Science and Business Media LLC
Date: 03-01-2020
DOI: 10.1007/S00018-019-03435-4
Abstract: 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 ersity to give rise to transmissible Schwann cell cancers in devils on rare occasions.
Publisher: arXiv
Date: 2022
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2020
DOI: 10.1101/831404
Abstract: Immune checkpoint immunotherapy has revolutionized medicine, but translational success for new treatments remains low. Around 40% of humans and Tasmanian devils ( Sarcophilus harrisii ) develop cancer in their lifetime, compared to less than 10% for most species. Additionally, devils are affected by two of the three known transmissible cancers in mammals. Unfortunately, little is known about of immune checkpoints in devils and other non-model species, largely due to a lack of species-specific reagents. We developed a simple cut-and-paste reagent development method applicable to any vertebrate species and show that immune checkpoint interactions are conserved across 160 million years of evolution. The inhibitory checkpoint molecule CD200 is highly expressed on devil facial tumor cells. We are the first to demonstrate that co-expression of CD200R1 can block CD200 expression. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can serve as models for understanding cancer and immunological tolerance.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-08-2019
Abstract: New understanding of Tasmanian devil facial tumors informs therapy and prevention
Publisher: Public Library of Science (PLoS)
Date: 09-12-2016
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.DCI.2017.07.004
Abstract: 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
Publisher: Springer Science and Business Media LLC
Date: 02-2022
Abstract: We present a measurement of the Cabibbo-Kobayashi-Maskawa unitarity triangle angle ϕ 3 (also known as γ ) using a model-independent Dalitz plot analysis of B + → D ( $$ {K}_S^0 $$ K S 0 h + h − ) h + , where D is either a D 0 or $$ \\overline{D} $$ D ¯ 0 meson and h is either a π or K . This is the first measurement that simultaneously uses Belle and Belle II data, combining s les corresponding to integrated luminosities of 711 fb − 1 and 128 fb − 1 , respectively. All data were accumulated from energy-asymmetric e + e − collisions at a centre-of-mass energy corresponding to the mass of the Υ(4 S ) resonance. We measure ϕ 3 = (78 . 4 ± 11 . 4 ± 0 . 5 ± 1 . 0)°, where the first uncertainty is statistical, the second is the experimental systematic uncertainty and the third is from the uncertainties on external measurements of the D -decay strong-phase parameters.
Publisher: Public Library of Science (PLoS)
Date: 27-04-2018
Publisher: Springer Science and Business Media LLC
Date: 02-08-2019
DOI: 10.1007/S00018-019-03259-2
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 ersity 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.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2021
Publisher: Cold Spring Harbor Laboratory
Date: 07-09-2020
DOI: 10.1101/2020.09.06.274720
Abstract: Downregulation of major histocompatibility complex I (MHC-I) on tumor cells is a primary means of immune evasion by many types of cancer. Additionally, MHC-I proteins are a primary target of immune-mediated transplant rejection. Transmissible tumors that overcome allograft rejection mechanisms and evade anti-tumor immunity have killed thousands of wild Tasmanian devils ( Sarcophilus harrisii ). Interferon gamma (IFNG) upregulates surface MHC-I expression on devil facial tumor (DFT) cells but is not sufficient to induce tumor regressions. Transcriptome analysis of IFNG-treated DFT cells revealed strong upregulation of NLRC5 , a master regulator of MHC-I in humans and mice. To explore the role of NLRC5 in transmissible cancers, we developed DFT cell lines that constitutively overexpress NLRC5. Transcriptomic results suggest that the role of NLRC5 as a master regulator of MHC-I is conserved in devils. Furthermore, NLRC5 was shown to drive the expression of many components of the antigen presentation pathway. To determine if MHC-I is a target of allogeneic immune responses, we tested serum from devils with anti-DFT responses including natural DFT regressions against DFT cells. Antibody binding occurred with cells treated with IFNG and overexpressed NLRC5. However, CRISPR/Cas9-mediated knockout of MHC-I subunit beta-2-microglobulin ( B2M ) eliminated antibody binding to DFT cells. Consequently, MHC-I could be identified as a target for anti-tumor and allogeneic immunity and provides mechanistic insight into MHC-I expression and antigen presentation in marsupials. 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.
Publisher: Microbiology Society
Date: 11-2022
DOI: 10.1099/JGV.0.001812
Abstract: The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil ( Sarcophilus harrisii ) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100 %. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2 and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as a vaccine platform for devils and potentially other marsupials.
Publisher: Bio-Protocol, LLC
Date: 2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-10-2016
DOI: 10.1158/2326-6066.IMM2016-B040
Abstract: Background: The potent immune modifier imiquimod (R-837) induces apoptosis of various tumor cell lines by mechanisms that are not fully understood. As a topical immunotherapy, imiquimod successfully activates tumor-specific cytotoxic responses via stimulation of TLR7 signaling pathways and antagonism of adenosine receptor mediated regulatory pathways. A role for imiquimod-induced tumor apoptosis in augmenting this response has not been defined, however it remains plausible that molecular changes may render the cells more susceptible to an anti-tumor response. An improved understanding of the pathways regulated by imiquimod in tumor cells will reveal whether this is likely the case. Devil facial tumor disease (DFTD) is a clonal transmissible cancer threatening the world's largest marsupial carnivore, the Tasmanian devil. DFTD evades both non-self and anti-cancer immune defenses to survive in new hosts, providing an ideal model for studying immunotherapeutic mechanisms. As we have previously shown that DFTD cells are sensitive to treatment with imiquimod, investigation of these effects could reveal new therapeutic strategies for DFTD, and will improve our understanding of this drug in cancer immunotherapy. Methods: To investigate the mechanisms of imiquimod action in tumor cells, DFTD cell lines and control fibroblast cell lines were treated in culture with imiquimod. Changes to cell viability were monitored by proliferation and cell death assays. Molecular changes to DFTD cells were assessed through RNA sequencing and proteomic mass spectrometry, and bioinfomatic techniques were employed to identify biological processes regulated by imiquimod. Major findings were confirmed by quantitative PCR. Results: Imiquimod treatment induces complete apoptosis of DFTD cells, but not fibroblasts, over a period of days. Transcriptomic and proteomic analysis revealed high constitutive expression of ER stress genes in DFTD cell lines, which were further augmented in response to imiquimod treatment. Up-regulation of genes required for ER-stress mediated apoptosis was also detected, suggesting that imiquimod induces apoptosis through exhaustion of the ER stress response. Molecular pathways associated with tumor growth and survival were modulated in the dying cells, and damage-associated alarmins were highly expressed. Conclusions: Our study provides the first whole transcriptome and proteome analysis of any imiquimod treated tumor cell line. By using DFTD cells as a tumor model, we have shown that imiquimod directly increases the apoptotic potential of tumor cells through augmentation of ER stress, while producing molecular changes consistent with reduced tumorigenicity. These effects were not replicated in fibroblasts, suggesting that constitutive activation of stress responses in tumor cells may impact their ability to cope with additional stressors. Our findings suggest that ER stress pathways are ideal targets for therapy against DFTD in our endangered Tasmanian devil. These data can also be applied for more rational use of imiquimod as an immunotherapeutic agent in human cancer. Citation Format: Amanda L. Patchett, Terry L. Pinfold, Cesar Tovar, Bruce Lyons, Gregory M. Woods. Imiquimod initiates tumor specific overload of the ER stress response in Tasmanian devil facial cancer cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival 2016 Sept 25-28 New York, NY. Philadelphia (PA): AACR Cancer Immunol Res 2016 (11 Suppl):Abstract nr B040.
Publisher: MDPI AG
Date: 28-12-2021
DOI: 10.3390/PATHOGENS11010027
Abstract: Devil Facial Tumour Disease (DFTD) is an emerging infectious disease that provides an excellent ex le of how diagnostic techniques improve as disease-specific knowledge is generated. DFTD manifests as tumour masses on the faces of Tasmanian devils, first noticed in 1996. As DFTD became more prevalent among devils, karyotyping of the lesions and their devil hosts demonstrated that DFTD was a transmissible cancer. The subsequent routine diagnosis relied on microscopy and histology to characterise the facial lesions as cancer cells. Combined with immunohistochemistry, these techniques characterised the devil facial tumours as sarcomas of neuroectodermal origin. More sophisticated molecular methods identified the origin of DFTD as a Schwann cell, leading to the Schwann cell-specific protein periaxin to discriminate DFTD from other facial lesions. After the discovery of a second facial cancer (DFT2), cytogenetics and the absence of periaxin expression confirmed the independence of the new cancer from DFT1 (the original DFTD). Molecular studies of the two DFTDs led to the development of a PCR assay to differentially diagnose the cancers. Proteomics and transcriptomic studies identified different cell phenotypes among the two DFTD cell lines. Phenotypic differences were also reflected in proteomics studies of extracellular vesicles (EVs), which yielded an early diagnostic marker that could detect DFTD in its latent stage from serum s les. A mesenchymal marker was also identified that could serve as a serum-based differential diagnostic. The emergence of two transmissible cancers in one species has provided an ideal opportunity to better understand transmissible cancers, demonstrating how fundamental research can be translated into applicable and routine diagnostic techniques.
Publisher: Elsevier BV
Date: 02-2023
Publisher: arXiv
Date: 2022
Publisher: Wiley
Date: 21-03-2021
DOI: 10.1111/IMCB.12451
Abstract: 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 erse 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.
Publisher: Impact Journals, LLC
Date: 23-03-2018
Location: Australia
Location: Australia
No related grants have been discovered for Amanda Patchett.