ORCID Profile
0000-0001-6409-3881
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: 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: 14-04-2020
DOI: 10.1038/S41467-020-15615-Z
Abstract: Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat’s antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: EMBO
Date: 29-08-2019
Publisher: Elsevier
Date: 2010
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Public Library of Science (PLoS)
Date: 28-01-2015
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
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: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.YDBIO.2015.05.023
Abstract: ROBO2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations in humans and mice leading to supernumerary kidneys. Previous studies have established that the number and position of UB outgrowths is determined by the domain of metanephric mesenchymal Gdnf expression, which is expanded anteriorly in Robo2 mouse mutants. To clarify how this phenotype arises, we used high-resolution 3D imaging to reveal an increase in the number of nephrogenic cord cells, leading to extension of the metanephric mesenchyme field in Robo2-null mouse embryos. Ex vivo experiments suggested a dependence of this effect on proliferative signals from the Wolffian duct. Loss of Robo2 resulted in a failure of the normal separation of the mesenchyme from the Wolffian duct/ureteric epithelium, suggesting that aberrant juxtaposition of these two compartments in Robo2-null mice exposes the mesenchyme to abnormally high levels of proliferative stimuli. Our data suggest a new model in which SLIT-ROBO signalling acts not by attenuating Gdnf expression or activity, but instead by limiting epithelial/mesenchymal interactions in the nascent metanephros and restricting the extent of the nephrogenic field. These insights illuminate the aetiology of multiplex kidney formation in human in iduals with ROBO2 mutations.
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: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Elsevier BV
Date: 05-2017
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: 11-2014
DOI: 10.1016/J.YDBIO.2014.08.037
Abstract: The issues of whether and how some organs coordinate their size and shape with the blueprint of the embryo axis, while others appear to regulate their morphogenesis autonomously, remain poorly understood. Mutations in Ift144, encoding a component of the trafficking machinery of primary cilia assembly, result in a range of embryo patterning defects, affecting the limbs, skeleton and neural system. Here, we show that embryos of the mouse mutant Ift144(twt) develop gonads that are larger than wild-type. Investigation of the early patterning of the urogenital ridge revealed that the anterior-posterior domain of the gonad/mesonephros was extended at 10.5 dpc, with no change in the length of the metanephros. In XY embryos, this extension resulted in an increase in testis cord number. Moreover, we observed a concomitant extension of the trunk axis in both sexes, with no change in the length of the tail domain or somite number. Our findings support a model in which: (1) primary cilia regulate embryonic trunk elongation (2) the length of the trunk axis determines the size of the urogenital ridges and (3) the gonad domain is partitioned into a number of testis cords that depends on the available space, rather than being ided a predetermined number of times to generate a specific number of cords.
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2010
Abstract: KLF1 regulates a erse suite of genes to direct erythroid cell differentiation from bipotent progenitors. To determine the local cis -regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as Hbb-b1 , but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of alpha- and beta-globin protein chains, heme biosynthesis, coordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment.
Publisher: Oxford University Press (OUP)
Date: 08-2013
DOI: 10.1095/BIOLREPROD.113.110155
Abstract: MicroRNAs are important regulators of developmental gene expression, but their contribution to fetal gonad development is not well understood. We have identified the evolutionarily conserved gonadal microRNAs miR-202-5p and miR-202-3p as having a potential role in regulating mouse embryonic gonad differentiation. These microRNAs are expressed in a sexually dimorphic pattern as the primordial XY gonad differentiates into a testis, with strong expression in Sertoli cells. In vivo, ectopic expression of pri-miR-202 in XX gonads did not result in molecular changes to the ovarian determination pathway. Expression of the primary transcript of miR-202-5p/3p remained low in XY gonads in a conditional Sox9-null mouse model, suggesting that pri-miR-202 transcription is downstream of SOX9, a transcription factor that is both necessary and sufficient for male sex determination. We identified the pri-miR-202 promoter that is sufficient to drive expression in XY but not XX fetal gonads ex vivo. Mutation of SOX9 and SF1 binding sites reduced ex vivo transactivation of the pri-miR-202 promoter, demonstrating that pri-miR-202 may be a direct transcriptional target of SOX9/SF1 during testis differentiation. Our findings indicate that expression of the conserved gonad microRNA, miR-202-5p/3p, is downstream of the testis-determining factor SOX9, suggesting an early role in testis development.
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: 05-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2023
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Elanor Wainwright.