ORCID Profile
0000-0001-6143-9285
Current Organisations
Centre for Cancer Biology
,
University of South Australia
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Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Biochemistry and Cell Biology | Signal Transduction | Cell Development, Proliferation and Death
Publisher: American Chemical Society (ACS)
Date: 09-2020
Publisher: Frontiers Media SA
Date: 29-06-2022
Abstract: While it is now well appreciated that the extracellular matrix (ECM) exerts biomechanical cues that direct critical cellular behavior, including cell proliferation, differentiation, migration, and survival, the molecular mechanisms underlying these cues remain mysterious. It has long been known that the ECM is also a source of biochemical cues that influence these processes, but the way these interact with ECM biomechanics also remains largely unknown. The systematic study of these relationships has been h ered by a paucity of models and the tools to interrogate them. Studies of complex models and tissue s les employing techniques such as atomic force microscopy (AFM) have informed much of our current understanding of how mechanical cues are transduced by the ECM and how cells respond to them. However, key observations made using such complex systems cannot be reliably assigned to the ECM or its components without a precise understanding of how these components respond to and exert mechanical force at the nanoscale – the scale at which in idual cells respond. To address this knowledge gap, we used AFM to study the nanomechanical properties of a simple model, consisting only of type I collagen, the most abundant component of the ECM. Intriguingly, our data show bimodal distribution that is entirely attributable to type I collagen, greatly simplifying the interpretation of these studies. Furthermore, we examined the nanomechanical influence of tissue fixation by protein cross-linking, an approach commonly used in research and medical histopathology, revealing a significant and non-uniform distortion of the nanomechanical profile of fixed s les, which has the potential to introduce artifacts into the nanomechanical characterization of tissues. In contrast to the clear observation of mechanical differences induced by cross-linking, Fourier-transform infrared (FTIR) spectroscopy revealed only subtle alterations to the chemical signature of the collagen, highlighting the importance of nanomechanical approaches for the complete characterization of model systems and tissues.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2015
DOI: 10.1038/ONC.2015.66
Abstract: The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.
Publisher: Bioscientifica
Date: 04-2023
DOI: 10.1530/JME-22-0174
Abstract: The tumor microenvironment is a dynamic ecosystem of stromal and immune cells that, under the influence of cancer cells, govern biochemical signaling, mechanical signaling via production and remodeling of the extracellular matrix (ECM), formation of vascular networks, and ultimately promotion of tumor growth. In breast cancer, hormone receptor-mediated signaling is a key coordinator of cancer cell proliferation and invasiveness not only through cell-autonomous means but also via cancer cell–stroma cross-talk. In the absence of hormone receptors, a different microenvironment landscape emerges, which comes with its own challenges for therapy. This review summarizes the current knowledge regarding the associations of hormone receptor profiles with composition of the microenvironment, how hormones directly influence stromal cells, immune cells and cells associated with the vasculature, and the paracrine mechanisms that lead to the formation of a tumor-promoting ECM.
Publisher: Informa UK Limited
Date: 17-02-2020
Publisher: Wiley
Date: 08-11-2016
DOI: 10.1002/DVG.22988
Abstract: The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream of the RhoA small GTP-binding protein. As a result, they have key roles in regulating cell morphology and proliferation, and have been implicated in numerous pathological conditions and diseases including hypertension and cancer. Here we describe the generation of a gene-targeted mouse line that enables CRE-inducible expression of a conditionally-active fusion between the ROCK2 kinase domain and the hormone-binding domain of a mutated estrogen receptor (ROCK2:ER). This two-stage system of regulation allows for tissue-selective expression of the ROCK2:ER fusion protein, which then requires administration of estrogen analogues such as tamoxifen or 4-hydroxytamoxifen to elicit kinase activity. This conditional gain-of-function system was validated in multiple tissues by crossing with mice expressing CRE recombinase under the transcriptional control of cytokeratin14 (K14), murine mammary tumor virus (MMTV) or cytochrome P450 Cyp1A1 (Ah) promoters, driving appropriate expression in the epidermis, mammary or intestinal epithelia respectively. Given the interest in ROCK signaling in normal physiology and disease, this mouse line will facilitate research into the consequences of ROCK activation that could be used to complement conditional knockout models. Birth Defects Research (Part A) 106:636-646, 2016. © 2016 Wiley Periodicals, Inc.
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: Springer Science and Business Media LLC
Date: 06-06-2015
Publisher: Springer Science and Business Media LLC
Date: 07-2014
DOI: 10.1007/S10911-014-9323-Y
Abstract: Cancer stem cells are believed to be a subset of heterogeneous tumour cells responsible for tumour initiation, growth, local invasion, and metastasis. In breast cancer, numerous factors have been implicated in regulation of cancer stem cells, but there is still a paucity of information regarding precise molecular and cellular mechanisms guiding their pathobiology. Components of both the adaptive and the innate immune system have been shown to play a crucial role in supporting breast cancer growth and spread, and recently some immune mediators, both molecules and cells, have been reported to influence breast cancer stem cell biology. This review summarises a small, pioneering body of evidence for the potentially important function of the "immuniche" in maintaining and supporting breast cancer stem cells.
Publisher: IntechOpen
Date: 18-03-2019
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2021
DOI: 10.1101/2021.02.03.425513
Abstract: The 14-3-3 family of proteins have roles in regulating several key cellular processes. While their significant structural and functional homology had informed the idea that these proteins acted redundantly, it is now becoming clear that in idual family members may have tissue and context specific functions, highlighting the need for a more nuanced understanding of these important proteins. Here, we demonstrate that mice deficient in 14-3-3ζ exhibit developmental defects of the mammary epithelium, associated with dysregulation of key transcription factors involved in the maintenance of mammary stem cell populations. We believe that this model will be prove useful for investigating the role of 14-3-3ζ in the maintenance of mammary stem cell populations and elucidating the transcriptional networks driving specification of the mammary epithelium.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2020
DOI: 10.1038/S41556-020-0523-Y
Abstract: It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.
Publisher: Informa UK Limited
Date: 11-05-2016
Publisher: Springer Science and Business Media LLC
Date: 04-06-2020
Publisher: Springer International Publishing
Date: 2021
Publisher: Rockefeller University Press
Date: 14-04-2020
DOI: 10.1084/JEM.20190634
Abstract: Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2017
Publisher: The Company of Biologists
Date: 15-12-2020
DOI: 10.1242/JCS.247783
Abstract: The tissue microenvironment supports normal tissue function and regulates the behaviour of parenchymal cells. Tumour cell behaviour, on the other hand, erges significantly from that of their normal counterparts, rendering the microenvironment hostile to tumour cells. To overcome this problem, tumours can co-opt and remodel the microenvironment to facilitate their growth and spread. This involves modifying both the biochemistry and the biophysics of the normal microenvironment to produce a tumour microenvironment. In this Cell Science at a Glance article and accompanying poster, we outline the key processes by which epithelial tumours influence the establishment of the tumour microenvironment. As the microenvironment is populated by genetically normal cells, we discuss how controlling the microenvironment is both a significant challenge and a key vulnerability for tumours. Finally, we review how new insights into tumour–microenvironment interactions has led to the current consensus on how these processes may be targeted as novel anti-cancer therapies.
Publisher: Wiley
Date: 25-05-2022
Abstract: To fully investigate cellular responses to stimuli and perturbations within tissues, it is essential to replicate the complex molecular interactions within the local microenvironment of cellular niches. Here, the authors introduce Alginate‐based tissue engineering (ALTEN), a biomimetic tissue platform that allows ex vivo analysis of explanted tissue biopsies. This method preserves the original characteristics of the source tissue's cellular milieu, allowing multiple and erse cell types to be maintained over an extended period of time. As a result, ALTEN enables rapid and faithful characterization of perturbations across specific cell types within a tissue. Importantly, using single‐cell genomics, this approach provides integrated cellular responses at the resolution of in idual cells. ALTEN is a powerful tool for the analysis of cellular responses upon exposure to cytotoxic agents and immunomodulators. Additionally, ALTEN's scalability using automated microfluidic devices for tissue encapsulation and subsequent transport, to enable centralized high‐throughput analysis of s les gathered by large‐scale multicenter studies, is shown.
Start Date: 03-2022
End Date: 12-2025
Amount: $436,600.00
Funder: Australian Research Council
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