ORCID Profile
0000-0002-0473-5392
Current Organisation
University of South Australia
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: INIST-CNRS
Date: 06-2013
DOI: 10.4267/2042/51042
Publisher: Informa UK Limited
Date: 08-2008
DOI: 10.4161/CC.6443
Abstract: The TGFbetas are a family of pleiotropic cytokines that mediate erse effects including the regulation of cell cycle progression, apoptosis, tissue remodelling and epithelial-mesenchymal transition (EMT). These erse effects allow the TGFbetas to play multiple and even opposing roles in different contexts during embryonal development, tissue homeostasis and cancer progression. We recently reported that the protein tyrosine phosphatase Pez is a novel inducer of TGFbeta signaling, regulating EMT and organogenesis in developing zebrafish embryos, and leading to TGFbeta-mediated EMT when overexpressed in vitro in epithelial MDCK cells. A number of mutations in Pez have been shown to be associated with breast and colorectal cancers, although the effect of these mutations on Pez function and their contribution to cancer progression remains unclear. Our finding that Pez regulates TGFbeta signaling is therefore of interest not only in the context of identifying a novel upstream regulator of TGFbeta signaling, but also in implicating the dysregulation of TGFbeta signaling as a possible link between Pez mutation and cancer progression. Here we discuss the implications of our research, in the context of dysregulation of TGFbeta signaling in cancer and other human pathologies.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2020
DOI: 10.1038/S41580-020-0237-9
Abstract: Epithelial–mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a erse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by ‘the EMT International Association’ (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining ersity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2021
DOI: 10.1038/S41419-021-03688-7
Abstract: Kidney disease progression can be affected by Na + abundance. A key regulator of Na + homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na + transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na + induced damage remain poorly understood. Here we show that a high Na + diet compromised kidney function in Nedd4-2 -deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na + rescued kidney disease in Nedd4-2 -deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na + homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.
Publisher: Elsevier BV
Date: 06-2022
Publisher: The Company of Biologists
Date: 2013
DOI: 10.1242/JCS.122275
Abstract: The miR-200 family is a key regulator of EMT, however its role in controlling the transition between cancer stem cell-like and non-stem cell-like phenotypes is not well understood. We utilized immortalized human mammary epithelial cells (HMLE) to investigate the regulation of the miR-200 family during their conversion to a stem-like phenotype. HMLE cells were found to be capable of spontaneous conversion from a non-stem to a stem-like phenotype and this conversion was accompanied by the loss of miR-200 expression. Stem-like cell fractions isolated from metastatic breast cancers also displayed loss of miR-200 indicating similar molecular changes may occur during breast cancer progression. The phenotypic change observed in HMLE cells was directly controlled by miR-200 as restoration of its expression decreased stem-like properties while promoting a transition to an epithelial phenotype. Investigation of the mechanisms controlling miR-200 expression revealed both DNA methylation and histone modifications were significantly altered in the stem-like and non-stem phenotypes. In particular, in the stem-like phenotype, the miR-200b-200a-429 cluster was silenced primarily through polycomb group-mediated histone modifications whereas the miR-200c-141 cluster was repressed by DNA methylation. These results indicate that the miR-200 family plays a critical role in the transition between stem-like and non-stem phenotypes and that distinct epigenetic-based mechanisms regulate each miR-200 gene in this process. Therapy targeted against miR-200 family members and epigenetic modifications may therefore be applicable to breast cancer.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.CONTRACEPTION.2013.11.002
Abstract: Sino-implant (II) is a two-rod subcutaneous contraceptive implant used up to 4 years, containing 150 mg of levonorgestrel. We conducted two observational studies of Sino-implant (II) to evaluate its performance in routine service delivery settings. We enrolled 1326 women age 18-44 who had Sino-implant (II) inserted at clinics in Pakistan and Kenya. Women were followed-up using either an active or passive follow-up scheme in each study. Study outcomes were: one-year cumulative pregnancy and discontinuation rates rates of insertion and removal complications adverse event and side effect rates reasons for discontinuation and implant acceptability and satisfaction with clinic services. A total of 754 women returned for at least one follow-up visit. The overall Pearl pregnancy rate was 0.4 per 100 woman-years [95% confidence interval (CI) 0.1, 0.9] resulting from 1 confirmed post-insertion pregnancy in Kenya and 4 in Pakistan. Country-specific Pearl rates were 0.2 (95% CI 0.0, 0.9) in Kenya and 0.6 (95% CI 0.2, 1.6) in Pakistan. The total cumulative 12-month probability of removal was 7.6% (95% CI 6.1, 9.1), with country-specific removal probabilities of 3.7% in Kenya (95% CI 2.1, 5.3) and 10.8% in Pakistan (95% CI 8.5, 13.2). Four serious adverse events occurred in Kenya and none occurred in Pakistan one SAE (an ectopic pregnancy) was possibly related to Sino-implant (II). Most women in both countries said they would recommend the implant to others. The results from these studies reveal high effectiveness and favorable safety and acceptability during the first year of use of Sino-implant. The favorable Sino-implant (II) findings from Kenya and Pakistan provide further evidence from disparate regions that Sino-implant (II) is safe, effective and acceptable during routine service delivery.
Publisher: Life Science Alliance, LLC
Date: 03-08-2023
Abstract: Epithelial–mesenchymal transition is essential for tissue patterning and organization. It involves both regulation of cell motility and alterations in the composition and organization of the ECM—a complex environment of proteoglycans and fibrous proteins essential for tissue homeostasis, signaling in response to chemical and biomechanical stimuli, and is often dysregulated under conditions such as cancer, fibrosis, and chronic wounds. Here, we demonstrate that basonuclin-2 (BNC2), a mesenchymal-expressed gene, that is, strongly associated with cancer and developmental defects across genome-wide association studies, is a novel regulator of ECM composition and degradation. We find that at endogenous levels, BNC2 controls the expression of specific collagens, matrix metalloproteases, and other matrisomal components in breast cancer cells, and in fibroblasts that are primarily responsible for the production and processing of the ECM within the tumour microenvironment. In so doing, BNC2 modulates the motile and invasive properties of cancers, which likely explains the association of high BNC2 expression with increasing cancer grade and poor patient prognosis.
Publisher: American Society for Cell Biology (ASCB)
Date: 15-05-2011
Abstract: Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 30-06-2015
DOI: 10.1158/0008-5472.CAN-15-0287
Abstract: microRNAs (miRNA) are well suited to the task of regulating gene expression networks, because any given miRNA has the capacity to target dozens, if not hundreds, of genes. The simultaneous targeting of multiple genes within a pathway may enable miRNAs to more strongly regulate the pathway, or to achieve more subtle control through the targeting of distinct subnetworks of genes. Therefore, as our capacity to discover miRNA targets en masse increases, so must our consideration of the complex networks in which these genes participate. We highlight recent studies in which the comprehensive identification of targets has been used to elucidate miRNA-regulated gene networks in cancer, focusing especially upon miRNAs such as members of the miR-200 family that regulate epithelial–mesenchymal transition (EMT), a reversible phenotypic switch whereby epithelial cells take on the more invasive properties of their mesenchymal counterparts. These studies have expanded our understanding of the roles of miRNAs in EMT, which were already known to form important regulatory loops with key transcription factors to regulate the epithelial or mesenchymal properties of cells. Cancer Res 75(13) 2594–9. ©2015 AACR.
Publisher: Wiley
Date: 16-12-2021
Abstract: Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit in idual compensatory RTK—requiring knowledge of which RTKs are upregulated in any given tumour—strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is a common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking—in particular, aberrant post‐translational modifications in cancers that contribute to dysregulated endosomal trafficking—could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1593/NEO.121828
Publisher: Springer Science and Business Media LLC
Date: 06-12-2020
DOI: 10.1038/S41416-019-0669-1
Abstract: Stathmin mediates cell migration and invasion in vitro, and metastasis in vivo. To investigate stathmin’s role on the metastatic process, we performed integrated mRNA–miRNA expression analysis to identify pathways regulated by stathmin. MiRNA and gene arrays followed by miRNA-target-gene integration were performed on stathmin-depleted neuroblastoma cells (Ctrl shRNA vs. Stmn Seq2 shRNA ). The expression of the predicted target PTPN14 was evaluated by RT-qPCR, western blot and immunohistochemistry. Gene-silencing technology was used to assess the role of PTPN14 on proliferation, migration, invasion and signalling pathway. Stathmin levels modulated the expression of genes and miRNA in neuroblastoma cells, leading to a deregulation of migration and invasion pathways. Consistent with gene array data, PTPN14 mRNA and protein expression were downregulated in stathmin- depleted neuroblastoma cells and xenografts. In two independent neuroblastoma cells, suppression of PTPN14 expression led to an increase in cell migration and invasion. PTPN14 and stathmin expression did not act in a feedback regulatory loop in PTPN14- depleted cells, suggesting a complex interplay of signalling pathways. The effect of PTPN14 on YAP pathway activation was cell-type dependent. Our findings demonstrate that stathmin levels can regulate PTPN14 expression, which can modulate neuroblastoma cell migration and invasion.
Publisher: BMJ
Date: 26-02-2019
DOI: 10.1136/ANNRHEUMDIS-2018-213799
Abstract: We aimed to understand the role of the tyrosine phosphatase PTPN14—which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol—in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Gene rotein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis. RA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFβ-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP—but not of a non-YAP-interacting PTPN14 mutant—enhanced SMAD reporter activity. YAP promoted TGFβ-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity. In RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-02-2015
DOI: 10.1126/SCISIGNAL.2005547
Abstract: Without the protein phosphatase PTPN14, tumor cells secrete more prometastatic factors and send more growth-promoting receptors to the surface.
Publisher: EMBO
Date: 06-06-2018
Publisher: Public Library of Science (PLoS)
Date: 25-09-2013
Publisher: Springer Science and Business Media LLC
Date: 21-02-2010
DOI: 10.1038/NCB0310-209
Abstract: The microRNA miR-9 is induced by Myc in breast cancer cells where it targets the major epithelial adherens junction protein, E-cadherin. This primes the cancer cells for epithelial-mesenchymal transition (EMT) and also stimulates angiogenesis in tumours.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.BBAPAP.2013.03.014
Abstract: The secretome is the collection of all macromolecules secreted by a cell, and is a vital aspect of cell-cell communication in eukaryotes. In cancer, tumour cells often display secretomes with altered composition compared to the normal tissue from which they are derived. These changes can contribute to the acquisition and maintenance of the recognised hallmarks of cancer. In addition, evidence is emerging for a more sophisticated role for the tumour secretome in cancer, with significant implications for malignant disease progression. In this review, we highlight recent advances in our understanding of factors contributing to secretome alterations in cancer, including genetic mutations, microRNA-based regulation and the influence of the tumour microenvironment. The contribution of secreted factors in maintenance and function of cancer stem cells, and of tumour-derived factors in specification of a pre-metastatic niche are also discussed. Collectively, evidence from the current literature suggests that the tumour secretome, consisting of factors derived from cancer stem cells, non-stem cells and the surrounding stroma, plays a deterministic role in cancer progression, and may constitute a key therapeutic target in many cancers. This article is part of a Special Issue entitled: An Updated Secretome.
Publisher: EMBO
Date: 28-07-2014
Abstract: The micro RNA s of the miR‐200 family maintain the central characteristics of epithelia and inhibit tumor cell motility and invasiveness. Using the Ago‐ HITS ‐ CLIP technology for transcriptome‐wide identification of direct micro RNA targets in living cells, along with extensive validation to verify the reliability of the approach, we have identified hundreds of miR‐200a and miR‐200b targets, providing insights into general features of mi RNA target site selection. Gene ontology analysis revealed a predominant effect of miR‐200 targets in widespread coordinate control of actin cytoskeleton dynamics. Functional characterization of the miR‐200 targets indicates that they constitute subnetworks that underlie the ability of cancer cells to migrate and invade, including coordinate effects on Rho‐ ROCK signaling, invadopodia formation, MMP activity, and focal adhesions. Thus, the miR‐200 family maintains the central characteristics of the epithelial phenotype by acting on numerous targets at multiple levels, encompassing both cytoskeletal effectors that control actin filament organization and dynamics, and upstream signals that locally regulate the cytoskeleton to maintain cell morphology and prevent cell migration.
Publisher: Rockefeller University Press
Date: 07-01-2021
Abstract: Receptor degradation terminates signaling by activated receptor tyrosine kinases. Degradation of EGFR occurs in lysosomes and requires the switching of RAB5 for RAB7 on late endosomes to enable their fusion with the lysosome, but what controls this critical switching is poorly understood. We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. The rapid association of phospho-Y374-PKCδ with EGFR-containing endosomes is diminished by PTPN14, which dephosphorylates phospho-Y374-PKCδ. In triple-negative breast cancer cells, the FER-dependent phosphorylation of PKCδ enhances EGFR signaling and promotes anchorage-independent cell growth. Importantly, increased Y374-PKCδ phosphorylation correlating with arrested late endosome maturation was identified in ∼25% of triple-negative breast cancer patients, suggesting that dysregulation of this pathway may contribute to their pathology.
No related grants have been discovered for Yeesim Khew-Goodall.