A5026169079- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- CAR-T cell therapy research
- Ubiquitin and proteasome pathways
- Cell death mechanisms and regulation
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- interferon and immune responses
- Chronic Lymphocytic Leukemia Research
- Immune Cell Function and Interaction
- Nanoparticle-Based Drug Delivery
- Cytomegalovirus and herpesvirus research
- Lymphoma Diagnosis and Treatment
- PARP inhibition in cancer therapy
- Protein Degradation and Inhibitors
- Hippo pathway signaling and YAP/TAZ
- Developmental Biology and Gene Regulation
- T-cell and B-cell Immunology
- Cytokine Signaling Pathways and Interactions
- Glioma Diagnosis and Treatment
- Immune Response and Inflammation
- Synthesis and Biological Evaluation
- PI3K/AKT/mTOR signaling in cancer
- Invertebrate Immune Response Mechanisms
- Enzyme function and inhibition
The University of Melbourne
2018-2025
Walter and Eliza Hall Institute of Medical Research
2018-2025
La Trobe University
2018-2019
Abstract Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal 12 different mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation response to chemotherapeutics 15 human cell lines colon cancer–derived organoids culture. Moreover, mutant TP53/TRP53 impair...
Abstract Mutant TP53 proteins are thought to drive the development and sustained expansion of cancers at least in part through loss wild-type (wt) tumour suppressive functions. Therefore, compounds that can restore wt functions mutant expected inhibit tumours expressing TP53. APR-246 has been reported exert such effects malignant cells is currently undergoing clinical trials several cancer types. However, there evidence may also kill do not express To support it important understand its...
TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal killing by BH3-mimetics through an unknown mechanism. Here, we report activated following induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward...
Abstract BH3-mimetic drugs are an anti-cancer therapy that can induce apoptosis in malignant cells by directly binding and inhibiting pro-survival proteins of the BCL-2 family. The drug venetoclax, which targets BCL-2, has been approved for treatment chronic lymphocytic leukaemia acute myeloid regulatory authorities worldwide. However, while most patients initially respond well, resistance relapse on this is emerging critical issue clinic. Though some studies have begun uncovering factors...
Mutations in Trp53, prevalent human cancer, are reported to drive tumorigenesis through dominant-negative effects (DNEs) over wild-type TRP53 function as well neomorphic gain-of-function (GOF) activity. We show that five mutants do not accelerate lymphomagenesis on a TRP53-deficient background but strongly synergize with c-MYC overexpression manner distinguishes the hot spot Trp53 mutations. RNA sequencing revealed mutant DNE does globally repress disproportionately impacts subset of target...
Abstract Cas12a is a next-generation gene editing tool that enables multiplexed targeting. Here, we present mouse model constitutively expresses enhanced Acidaminococcus sp. ( enAsCas12a ) linked to an mCherry fluorescent reporter. We demonstrate efficient single and in vitro, using primary transformed cells from mice. further successful vivo editing, normal cancer-prone stem reconstitute the haematopoietic system of wild-type also compact, genome-wide knockout libraries, with four crRNAs...
Abstract CRISPR technologies have advanced cancer modelling in mice, but activation (CRISPRa) methods not been exploited this context. We establish a CRISPRa mouse ( dCas9a-SAM KI ) for inducing gene expression vivo and vitro. Using primary lymphocytes, we induce B cell restricted genes T cells vice versa, demonstrating the power of system. There are limited models aggressive double hit lymphoma. Therefore, transactivate pro-survival BCL-2 Eµ-Myc T/+ ;dCas9a-SAM KI/+ haematopoietic stem...
Abstract Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select prosurvival induce apoptosis have been developed for therapy. Venetoclax, which targets BCL-2, has effective as therapy patients with chronic lymphocytic leukemia, MCL-1–targeting extensively evaluated in preclinical studies a range blood cancers. Recently, BCL-W, relatively understudied member the protein family, reported be...
One fundamental property of a stem cell niche is the exchange molecular signals between its component cells. Niche models, such as Drosophila melanogaster testis, have been instrumental in identifying and studying conserved genetic factors that contribute to signalling. Here, we identify jam packed (jam), an allele Striatin interacting protein (Strip), which core member highly Striatin-interacting phosphatase kinase (STRIPAK) complex. In developing Strip cell-autonomously regulates...
Whole-genome screens using CRISPR technologies are powerful tools to identify novel tumour suppressors as well factors that impact responses of malignant cells anti-cancer agents. Applying this methodology lymphoma cells, we conducted a genome-wide screen inhibitors expansion induced by the suppressor TRP53. We discovered absence Arrestin domain containing 3 (ARRDC3) increases survival and long-term competitiveness MYC-driven when treated with agents activate Deleting Arrdc3 in mice caused...
Elevated Ras signalling is highly prevalent in human cancer; however, targeting Ras-driven cancers with pathway inhibitors often leads to undesirable side effects and drug resistance. Thus, identifying compounds that synergise would enable lower doses of the be used also decrease acquisition Here, a specialised chemical screen using Drosophila model cancer, we have identified reduce tumour size by synergising sub-therapeutic inhibitor trametinib, which targets MEK, mitogen-activated protein...
<p>Supplementary Figure S24 showing that removal of mutant TP53 does not impair the in vitro growth human colon cancer derived organoids</p>
<p>Supplementary Figure S3 showing that removal of mutant TP53 does not impair the ability diverse human cancer cell lines to adapt conditions stress</p>
<div>Abstract<p>Mutations in the tumor suppressor <i>TP53</i> cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal 12 different mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation response to chemotherapeutics 15 human cell lines colon cancer–derived organoids culture....
<p>Supplementary Figure S13 showing that mutant TP53 deficient human cancer cell lines retain the machinery to respond activation of wt TP53</p>
<p>Supplementary Figure S11 showing that removal of mutant TP53 does not cause a competitive growth disadvantage in diverse human cancer cell lines culture</p>
<p>Supplementary Figure S14 showing that CRISPR-HDR mediated conversion of mutant TP53 into wt causes a growth disadvantage in human cancer cell lines</p>