A5087306413- Cancer-related molecular mechanisms research
- Barrier Structure and Function Studies
- Neurological Disease Mechanisms and Treatments
- Immune Cell Function and Interaction
- Epigenetics and DNA Methylation
- Acute Myeloid Leukemia Research
- Cancer Immunotherapy and Biomarkers
- CRISPR and Genetic Engineering
- Cancer Cells and Metastasis
- Histone Deacetylase Inhibitors Research
- Cancer Genomics and Diagnostics
- CAR-T cell therapy research
- Lymphoma Diagnosis and Treatment
- RNA and protein synthesis mechanisms
- Gut microbiota and health
- Circular RNAs in diseases
- Advanced biosensing and bioanalysis techniques
- RNA modifications and cancer
- Enhanced Recovery After Surgery
- Drug Transport and Resistance Mechanisms
- Cell Adhesion Molecules Research
- Cell Image Analysis Techniques
- Immunotherapy and Immune Responses
- Cancer, Stress, Anesthesia, and Immune Response
- Microtubule and mitosis dynamics
The University of Melbourne
2018-2024
Peter MacCallum Cancer Centre
2021-2024
Victorian Comprehensive Cancer Centre
2018-2023
Abstract Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% all acute myeloid leukemias (AML). Limited clinical efficacy FLT3 inhibitors highlights need for alternative therapeutic modalities this subset disease. Using human and murine models FLT3-ITD–driven AML, we demonstrate that FLT3-ITD promotes serine synthesis uptake via ATF4-dependent transcriptional regulation genes de novo biosynthesis pathway neutral amino acid transport. Genetic or...
Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation stem cells (CSC). The tight junction (TJ) protein claudin-2 overexpressed in human where it enhances cell proliferation, colony formation, and chemoresistance vitro While several these biological processes are features CSC phenotype, role for regulation has not been identified. Here, we report that elevated expression stage II/III tumors associated with poor...
Oncogenic gene fusions are key drivers of cancer, yet most remain untargetable by current therapies. Here, we establish CRISPR-PspCas13b as a personalizable platform for systematic silencing various fusion transcripts. We reveal that recognition and cleavage the breakpoint sequence PspCas13b disrupts transcript, resulting in unexpected RNA nicking ligation near site, which generates out-of-frame, translation-incompetent This approach efficiently degrades canonical drug-resistant BCR::ABL1...
Cytotoxic lymphocytes are essential for anti-tumor immunity, and effective responses to cancer immunotherapy. Natural killer cell granule protein 7 (NKG7) is expressed at high levels in cytotoxic infiltrating tumors from patients treated with immunotherapy, but until recently, the role of this lymphocyte function was largely unknown. Unexpectedly, we found that highly CD8+ T cell-immunogenic murine colon carcinoma (MC38-OVA) grew an equal rate Nkg7 +/+ -/- littermate mice, suggesting NKG7...
The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognised in colorectal cancer (CRC). However, as most patients show limited intra-tumoral NK infiltration, improving our ability to identify those with high activity might aid dissecting the molecular features which underlie sensitivity. Here, a novel CRC-specific gene signature that infers load primary tissue samples was derived and validated multiple patient CRC cohorts. In contrast other signatures...
Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of treatment resistance tumour recurrence. However, due to the technical difficulty associated with studying such intra-tumoural heterogeneity, this phenomenon is seldom interrogated in conventional culture models. Here, we employ a fluorescent lineage technique termed "optical barcoding" (OBC) perform simultaneous longitudinal tracking spatio-temporal fate 64 patient-derived colorectal subclones....
ABSTRACT Patients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt enable successful surgical removal and reduce risk recurrence. Yet, majority patients progress treatment or recur following surgery, molecular mechanisms that contribute resistance remain poorly understood. Here, using a combination phenotypic,...
Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1-2 years treatment. We previously identified most common mechanism acquired in HGSOC date, transcriptional fusions involving ATP-binding cassette (ABC) transporter ABCB1, which has well established roles multidrug resistance. However, underlying biology fusion-positive cells, as how clonal interactions between...
ABSTRACT Single nucleotide variants (SNVs) are extremely prevalent in human cancers. For instance, KRAS mutations occur over 90% of pancreatic cancers and ∼40% colorectal Virtually all SNVs, most which remain clinically unactionable. The programmable RNA nuclease CRISPR-Cas13 has been deployed to specifically target RNAs such as overexpressed oncogenes fusion transcripts. However, silencing oncogenic SNVs with single-base precision remains challenging due the intrinsic mismatch tolerance...
Single-nucleotide variants (SNVs) are extremely prevalent in human cancers, although most of these remain clinically unactionable. The programmable RNA nuclease CRISPR-Cas13 has been deployed to specifically target oncogenic RNAs. However, silencing SNVs with single-base precision remains challenging due the intrinsic mismatch tolerance Cas13. Here, we show that introducing synthetic mismatches at precise positions spacer sequence enables de novo design guide RNAs [CRISPR (crRNAs)] strong...
Abstract The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognised in colorectal cancer (CRC). However, as most patients show limited intra-tumoral NK infiltration, improving our ability to identify those with high activity might aid dissecting the molecular features which could trigger strong response cell-mediated immune killing. Here, a novel CRC-specific gene signature capable inferring load primary tissue samples was derived and validated...
Abstract Activating FMS-like tyrosine kinase 3 ( FLT3 ) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy inhibitor monotherapy has highlighted the need for alternative therapeutic targets treatments FLT3-mutant AML. Using human murine models MLL-rearranged AML harbouring internal tandem duplication (FLT3-ITD) primary patient samples, we have demonstrated that FLT3-ITD promotes serine uptake...
<p>This file contains all supplemental Figures, as well legends for both Supplemental Figures and Tables, methods associated references</p>
<div>Abstract<p>Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation stem cells (CSC). The tight junction (TJ) protein claudin-2 overexpressed in human where it enhances cell proliferation, colony formation, and chemoresistance <i>in vitro</i>. While several these biological processes are features CSC phenotype, role for regulation has not been identified. Here, we report that elevated expression...
<p>This table contains the de-identified clinical data on all patients from Tissue microarray used in Figure 1 and S1.</p>
<p>This table contains the sequence of all primers used for qPCR, siren and shRNAs against claudin-2, as well details about miRNA mimics inhibitors in this work.</p>
<p>This table presents the Top 10 most enriched KEGG pathways identified from panel of miRNAs regulated by claudin-2, along with their enrichment score and p-value.</p>
<p>This table contains the de-identified clinical data on all patients from Tissue microarray used in Figure 1 and S1.</p>
<p>This table contains identified self-renewal target genes for the three candidate miRNA experimentally tested in our study, along with their prediction score. Only those targets score >0.85 are included.</p>
<p>This table contains the combined list of genes (Column I) involved in self-renewal processes that were used to analyze potential enrichments for miRNA targets. This was established using Gene Ontology keywords ('Self-renewal', columns A-B; 'Stem cell', C-D) or extracted from prior publications.</p>
<p>This table contains identified self-renewal target genes for the three candidate miRNA experimentally tested in our study, along with their prediction score. Only those targets score >0.85 are included.</p>
<div>Abstract<p>Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation stem cells (CSC). The tight junction (TJ) protein claudin-2 overexpressed in human where it enhances cell proliferation, colony formation, and chemoresistance <i>in vitro</i>. While several these biological processes are features CSC phenotype, role for regulation has not been identified. Here, we report that elevated expression...