Project description:The Tasmanian devil, a marsupial carnivore, is endangered due to the emergence of a clonally transmissible cancer known as Devil Facial Tumor Disease (DFTD). This fatal cancer is clonally derived and is an allograft transmitted between devils by biting. We performed a large-scale genetic analysis of DFTD with microsatellite genotyping, mitochondrial genome analysis, as well as deep sequencing of the DFTD transcriptome and miRNAs. These studies confirm that DFTD is a monophyletic clonally transmissible tumor, and suggest that the disease is of Schwann cell origin. On the basis of these results we have generated a diagnostic marker for DFTD, and identify a suite of genes of relevance to DFTD pathology and transmission. We provide a genomic dataset for the Tasmanian devil, which is applicable to cancer diagnosis, disease evolution and conservation biology. This submission contains only small RNA sequence data from this study. Small RNA (18 - 24 nt) sequences from 15 Tasmanian devil (Sarcophilus harrisii) tissue samples
Project description:Loss of MHC class I (MHC-I) antigen presentation in cancer cells can lead to immunotherapy resistance. Using a genome-wide CRISPR/Cas9 screen we identify a critical role for polycomb repressive complex 2 (PRC2) in the coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP). This evolutionarily conserved function of PRC2 promotes evasion of T-cell mediated immunity, enabling tumor transmission to non-histocompatible recipients in small cell lung cancer (SCLC) and Tasmanian Devil Facial Tumor. MHC-I APP gene promoters in MHC-I low cancers harbour bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine induced MHC-I APP gene upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological silencing of MHC-I expression highlights a conserved mechanism by which cancers arising from these primitive tissues coopt PRC2 activity to enable immune evasion.
Project description:The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the culprit molecular underpinnings, we designed an approach that combines sensitivity to drugs with an integrated systems-biology characterization. Sensitivity to inhibitors of the ERBB family of receptor tyrosine kinases correlated with their overexpression, suggesting a causative link. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to oncogenic signaling hubs including evolutionary conserved STAT3. Indeed, inhibition of ERBB blocked phosphorylation of STAT3 and arrested cancer cells. Blockade of ERBB signaling prevented tumor growth in a xenograft model and resulted in recovery of MHC-I gene expression. This link between the hyperactive ERBB-STAT3 axis and decreased MHC-I mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and lets us propose a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD.
Project description:The Tasmanian devil, a marsupial carnivore, is endangered due to the emergence of a clonally transmissible cancer known as Devil Facial Tumor Disease (DFTD). This fatal cancer is clonally derived and is an allograft transmitted between devils by biting. We performed a large-scale genetic analysis of DFTD with microsatellite genotyping, mitochondrial genome analysis, as well as deep sequencing of the DFTD transcriptome and miRNAs. These studies confirm that DFTD is a monophyletic clonally transmissible tumor, and suggest that the disease is of Schwann cell origin. On the basis of these results we have generated a diagnostic marker for DFTD, and identify a suite of genes of relevance to DFTD pathology and transmission. We provide a genomic dataset for the Tasmanian devil, which is applicable to cancer diagnosis, disease evolution and conservation biology. This submission contains only small RNA sequence data from this study.
Project description:Loss of MHC class I (MHC-I) antigen presentation in cancer cells can lead to immunotherapy resistance. Using a genome-wide CRISPR/Cas9 screen we identify a critical role for polycomb repressive complex 2 (PRC2) in the coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP). This evolutionarily conserved function of PRC2 promotes evasion of T-cell mediated immunity, enabling tumour transmission to non-histocompatible recipients in small cell lung cancer (SCLC) and Tasmanian Devil Facial Tumour. MHC-I APP gene promoters in MHC-I low cancers harbour bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine induced MHC-I APP gene upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological silencing of MHC-I expression highlights a conserved mechanism by which cancers arising from these primitive tissues coopt PRC2 activity to enable immune evasion.
Project description:Transmissible cancers are spread via the passage of malignant cells. The survival of the Tasmanian devil, the largest marsupial carnivore, is threatened by two independent transmissible cancers, devil facial tumour (DFT) 1 and devil facial tumour 2 (DFT2). To aid the development of a peptide vaccine and to interrogate how histocompatibility barriers can be overcome, we analysed the peptides bound to Major Histocompatibility Complex class I molecules from the Tasmanian devil and its transmissible tumours.
Project description:Purpose: Depict the landscape of epigenetic regulation in Tasmanian devil facial tumor biopsies. Differential analysis of healthy versus tumor biopsies highlighted 166 candidate genes with different DNA methylation levels in their promoters, which included the tumor-specific hypermethylated promoters of Estrogen Receptor 1 (ESR1) and the transcription factor GATA3.
