ORCID Profile
0000-0002-7814-4851
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Frontiers Media SA
Date: 20-08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1078-0432.CCR-18-3691
Abstract: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival (N = 5) or had a very short time to progression (N = 5). The majority of mixed OCCC (N = 6, 85.7%) and a small proportion of pure OCCC (N = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS (P = 0.0194 and 0.0395, respectively). Mutations in ARID1A, PIK3CA, PPP2R1A, and TP53 were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome.
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471185.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 07-08-2023
DOI: 10.1158/2159-8290.CD-23-0007
Abstract: Therapies that enhance anti-tumour immunity have altered the natural history of many cancers. Consequently, leveraging non-overlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase, METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signalling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that whilst METTL3 inhibition is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies overcome clones insensitive to the single agents. These data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinic.
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Springer Science and Business Media LLC
Date: 20-06-2019
DOI: 10.1038/S41467-019-10652-9
Abstract: Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient s les and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-04-2020
Abstract: Bromodomain and extraterminal domain (BET) proteins contribute to the pathogenesis of cancer and immune diseases through their effects on transcriptional regulation. BET proteins contain two nearly identical bromodomains, BD1 and BD2, structural modules that have attracted great interest as targets for drug development. First-generation drugs that inhibited both BD1 and BD2 showed promising therapeutic activity in preclinical models but proved to be less efficacious in clinical trials. Gilan et al. took a different approach and designed drugs that selectively inhibited BD1 or BD2 (see the Perspective by Filippakopoulos and Knapp). They found that BD1 and BD2 inhibitors altered gene expression in different ways and that BD2 inhibitors had greater therapeutic activity than BD1 inhibitors in preclinical models of inflammation and autoimmune disease. Science , this issue p. 387 see also p. 367
Publisher: Cold Spring Harbor Laboratory
Date: 21-12-2022
DOI: 10.1101/2022.12.20.521313
Abstract: S le multiplexing is often used to reduce cost and limit batch effects in single-cell RNA sequencing (scRNA-seq) experiments. A commonly used multiplexing technique involves tagging cells prior to pooling with a hashtag oligo (HTO) that can be sequenced along with the cells’ RNA to determine their s le of origin. Several tools have been developed to demultiplex HTO sequencing data and assign cells to s les. In this study, we critically assess the performance of seven HTO demultiplexing tools: hashedDrops, HTODemux, GMM-Demux, demuxmix, deMULTIplex, BFF and HashSolo . The comparison uses data sets where each s le has also been demultiplexed using genetic variants from the RNA, enabling comparison of HTO demultiplexing techniques against complementary data from the genetic “ground truth”. We find that all methods perform similarly where HTO labelling is of high quality, but methods that assume a bimodal counts distribution perform poorly on lower quality data. We also suggest heuristic approaches for assessing the quality of HTO counts in a scRNA-seq experiment.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6527802.V1
Abstract: AbstractPurpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( i N /i = 5) or had a very short time to progression ( i N /i = 5). Results: The majority of mixed OCCC ( i N /i = 6, 85.7%) and a small proportion of pure OCCC ( i N /i = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( i P /i = 0.0194 and 0.0395, respectively). Mutations in i ARID1A, PIK3CA, PPP2R1A /i , and i TP53 /i were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome. /
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Oxford University Press (OUP)
Date: 04-2020
Abstract: Schizosaccharomyces pombe is a model unicellular eukaryote with ties to the basic research, oenology and industrial biotechnology sectors. While most investigations into S. pombe cell biology utilize Leupold’s 972h- laboratory strain background, recent studies have described a wealth of genetic and phenotypic ersity within wild populations of S. pombe including stress resistance phenotypes which may be of interest to industry. Here we describe the genomic and transcriptomic characterization of Wilmar-P, an S. pombe isolate used for bioethanol production from sugarcane molasses at industrial scale. Novel sequences present in Wilmar-P but not in the laboratory S. pombe genome included multiple coding sequences with near-perfect nucleotide identity to Schizosaccharomyces octosporus sequences. Wilmar-P also contained a ∼100kb duplication in the right arm of chromosome III, a region harboring ght5+, the predominant hexose transporter encoding gene. Transcriptomic analysis of Wilmar-P grown in molasses revealed strong downregulation of core environmental stress response genes and upregulation of hexose transporters and drug efflux pumps compared to laboratory S. pombe. Finally, examination of the regulatory network of Scr1, which is involved in the regulation of several genes differentially expressed on molasses, revealed expanded binding of this transcription factor in Wilmar-P compared to laboratory S. pombe in the molasses condition. Together our results point to both genomic plasticity and transcriptomic adaptation as mechanisms driving phenotypic adaptation of Wilmar-P to the molasses environment and therefore adds to our understanding of genetic ersity within industrial fission yeast strains and the capacity of this strain for commercial scale bioethanol production.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471188
Abstract: Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471185
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Springer Science and Business Media LLC
Date: 08-12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6527802
Abstract: AbstractPurpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( i N /i = 5) or had a very short time to progression ( i N /i = 5). Results: The majority of mixed OCCC ( i N /i = 6, 85.7%) and a small proportion of pure OCCC ( i N /i = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( i P /i = 0.0194 and 0.0395, respectively). Mutations in i ARID1A, PIK3CA, PPP2R1A /i , and i TP53 /i were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471188.V1
Abstract: Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Elsevier BV
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471179.V1
Abstract: Supplementary methods
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471179
Abstract: Supplementary methods
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
No related grants have been discovered for Dane Vassiliadis.