ORCID Profile
0000-0001-9294-1745
Current Organisation
Garvan Institute of Medical Research
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Publisher: Frontiers Media SA
Date: 17-01-2020
Publisher: Springer Science and Business Media LLC
Date: 08-2013
DOI: 10.1186/BCR3461
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2022
DOI: 10.1101/2022.08.30.505945
Abstract: Metastatic cancer is responsible for the overwhelming majority of cancer-related deaths with metastatic tumors being the most common neoplasms affecting the central nervous system. One of the major factors regulating tumor biology is the tumor microenvironment. However, little is known about the cellular and non-cellular composition of metastatic brain tumors and how tumor cell ontogeny influences the metastatic brain tumor microenvironment. By integrating multiplex immunohistochemistry and histopathological analysis to investigate composition and the spatial relationship between neoplastic cells, infiltrating and brain resident immune cells and the extracellular matrix, we demonstrate that metastatic brain tumors exhibit differences in ECM deposition, compared with the most common primary brain tumor type, glioblastoma, and that the dominant immune cell types in metastatic brain tumors are immunosuppressive macrophages, which preferentially localize to ECM-rich stromal regions.
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2013
DOI: 10.1158/0008-5472.CAN-12-2447
Abstract: Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix–modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRβ, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient s les. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types. Cancer Res 73(2) 583–94. ©2012 AACR.
Publisher: Cambridge University Press (CUP)
Date: 03-2010
DOI: 10.1017/S1121189X00001524
Abstract: In iduals with schizophrenia have higher mortality rates compared to the general community. Apart from an increased risk of suicide, people with schizophrenia have an increased risk of death related to a wide range of comorbid physical conditions. There is evidence to suggest that much of this mortality is avoidable. The provision of assertive management of comorbid physical disorders has the potential to help close the differential mortality gap. While the primary data are robust, there is less empirical evidence to guide policy makers and service providers when dealing with these problems. Focused clinical programs aimed at reducing risk factors (e.g. smoking, obesity) and shared care between mental health teams and primary care providers can help reduce the burden of avoidable deaths. In light of recent evidence suggesting that the mortality gap has widened in recent decades, there is an urgent need to address the burden of avoidable deaths in those with serious mental illnesses.
Publisher: American Association for Cancer Research (AACR)
Date: 14-01-2016
DOI: 10.1158/0008-5472.CAN-15-2306
Abstract: Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no “cures” for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types. Cancer Res 76(2) 188–92. ©2016 AACR.
Publisher: Elsevier BV
Date: 2009
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428168
Abstract: SLC7A11 knockdown in PDAC CAFs does not affect glutamate secretion and is maintained in the presence of oxidative stress.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2012
DOI: 10.1038/ONC.2012.202
Abstract: The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC. Furthermore, we use rheology to measure the relative stiffness of modified collagen matrices and subcutaneous tumors, and show that LOX-induced collagen cross-linking results in stiffening of the matrix both in vitro and in vivo. We observe a strong association between matrix stiffness and activation of the FAK (focal adhesion kinase)/SRC-signaling pathway, with a stiffer environment resulting in increased FAK/SRC phosphorylation and a more proliferative and invasive phenotype. We are the first to show a direct relationship between LOX enzymatic activity and tissue stiffness, and to demonstrate a role for stiffness in driving CRC progression. Our findings provide significant evidence to suggest that therapeutic inhibition of LOX activity may provide a novel effective treatment option for patients with metastatic CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428165
Abstract: Confirmation of SLC7A11 knockdown in KPC tumour cells and CAFs and collagen fibril analysis in tumour sections at therapeutic model endpoint.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428159.V1
Abstract: Australian Pancreatic Cancer Genome Initiative International Cancer Genome Cohort patient cohort characteristics.
Publisher: EMBO
Date: 08-01-2014
Publisher: American Physiological Society
Date: 15-11-2013
Abstract: Colorectal cancer is the third most prevalent form of cancer worldwide and fourth-leading cause of cancer-related mortality, leading to ∼600,000 deaths annually, predominantly affecting the developed world. Lysyl oxidase is a secreted, extracellular matrix-modifying enzyme previously suggested to act as a tumor suppressor in colorectal cancer. However, emerging evidence has rapidly implicated lysyl oxidase in promoting metastasis of solid tumors and in particular colorectal cancer at multiple stages, affecting tumor cell proliferation, invasion, and angiogenesis. This emerging research has stimulated significant interest in lysyl oxidase as a strong candidate for developing and deploying inhibitors as functional efficacious cancer therapeutics. In this review, we discuss the rapidly expanding body of knowledge concerning lysyl oxidase in solid tumor progression, highlighting recent advancements in the field of colorectal cancer.
Publisher: Informa UK Limited
Date: 29-12-2018
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1038/S41467-021-23461-W
Abstract: Spatial proteomics has the potential to significantly advance our understanding of biology, physiology and medicine. Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) is a powerful tool in the spatial proteomics field, enabling direct detection and registration of protein abundance and distribution across tissues. MALDI-MSI preserves spatial distribution and histology allowing unbiased analysis of complex, heterogeneous tissues. However, MALDI-MSI faces the challenge of simultaneous peptide quantification and identification. To overcome this, we develop and validate HIT-MAP (High-resolution Informatics Toolbox in MALDI-MSI Proteomics), an open-source bioinformatics workflow using peptide mass fingerprint analysis and a dual scoring system to computationally assign peptide and protein annotations to high mass resolution MSI datasets and generate customisable spatial distribution maps. HIT-MAP will be a valuable resource for the spatial proteomics community for analysing newly generated and retrospective datasets, enabling robust peptide and protein annotation and visualisation in a wide array of normal and disease contexts.
Publisher: Portico
Date: 02-05-2012
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512931.V1
Abstract: Abstract Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428180.V1
Abstract: Validation of SLC7A11 antibodies and SLC7A11 knockdown in CAFs and PDAC cells in vitro.
Publisher: No publisher found
Date: 2017
DOI: 10.1016/J.CELREP.2017.08.095
Abstract: Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations. Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428165.V1
Abstract: Confirmation of SLC7A11 knockdown in KPC tumour cells and CAFs and collagen fibril analysis in tumour sections at therapeutic model endpoint.
Publisher: Wiley
Date: 04-2018
DOI: 10.1111/IEP.12269
Publisher: Springer Science and Business Media LLC
Date: 02-11-2017
Publisher: Impact Journals, LLC
Date: 26-05-2016
Publisher: Elsevier BV
Date: 07-2019
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.TRECAN.2016.05.004
Abstract: The relation between fibrosis and cancer has long been debated, specifically whether desmoplasia precedes, accompanies, or succeeds tumourigenesis, progression, and metastasis. Recent reports have published opposing data, adding to the perplexity. However, what is emerging is that it is likely the specific properties of the extracellular matrix (ECM) that determine the paradoxical nature of cancer-associated fibrosis.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2019
DOI: 10.1007/S10585-018-09953-Y
Abstract: The Metastasis Research Society (MRS) 17th Biennial conference on metastasis was held on the 1st to the 5th of August 2018 at Princeton University, NJ, USA. The meeting was held around themes addressing notable aspects of the understanding and treatment of metastasis and metastatic disease covering basic, translational, and clinical research. Importantly, the meeting was largely supported by our patient advocate partners including Susan G. Komen for the Cure, Theresa's Research Foundation and METAvivor. There were a total of 85 presentations from invited and selected speakers spread across the main congress and presentations from the preceding Young Investigator Satellite Meeting. Presentations are summarized in this report by session topic.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428159
Abstract: Australian Pancreatic Cancer Genome Initiative International Cancer Genome Cohort patient cohort characteristics.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428156.V1
Abstract: SLC7A11 expression in iCAFs, myCAFs and quiescent PSCs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428156
Abstract: SLC7A11 expression in iCAFs, myCAFs and quiescent PSCs.
Publisher: MDPI AG
Date: 13-10-2021
Abstract: The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in s les with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in s les correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-2021
Abstract: Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2013
DOI: 10.1158/0008-5472.CAN-12-2233
Abstract: Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer. Cancer Res 73(6) 1721–32. ©2012 AACR.
Publisher: Impact Journals, LLC
Date: 10-02-2017
Publisher: Elsevier BV
Date: 03-2022
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428177.V1
Abstract: Anti-proliferative effect of SLC7A11 knockdown in CAFs and the effect of SLC7A11 inhibition in MiaPaCa-2 PDAC cells and normal human pancreatic ductal epithelial (HPDE) cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428153
Abstract: SLC7A11 multivariate survival analysis parameters.
Publisher: Wiley
Date: 20-09-2023
DOI: 10.1002/PATH.6207
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428162
Abstract: List of antibodies
Publisher: Public Library of Science (PLoS)
Date: 20-01-2017
Publisher: eLife Sciences Publications, Ltd
Date: 22-05-2018
Publisher: Informa UK Limited
Date: 21-03-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428162.V1
Abstract: List of antibodies
Publisher: Impact Journals, LLC
Date: 10-07-2018
Publisher: Springer Science and Business Media LLC
Date: 24-07-2018
DOI: 10.1038/S41467-018-05220-6
Abstract: The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.
Publisher: Springer Science and Business Media LLC
Date: 12-2017
DOI: 10.1007/S10585-017-9872-8
Abstract: This commentary was written as a collaboration between the Board of the Metastasis Research Society and two patients with metastatic breast cancer. It was conceived in response to how preclinical scientific research is sometimes presented to non-scientists in a way that can cause stress and confusion. Translation of preclinical findings to the clinic requires overcoming multiple barriers. This is irrespective of whether the findings relate to exciting responses to new therapies or problematic effects of currently used therapies. It is important that these barriers are understood and acknowledged when research findings are summarized for mainstream reporting. To minimize confusion, patients should continue to rely on their oncology care team to help them interpret whether research findings presented in mainstream media have relevance for their in idual care. Researchers, both bench and clinical, should work together where possible to increase options for patients with metastatic disease, which is still in desperate need of effective therapeutic approaches.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2014
DOI: 10.1158/1078-0432.CCR-13-1059
Abstract: Pathologic organ fibrosis is a condition that can affect all major tissues and is typically ascribed to the excessive accumulation of extracellular matrix components, predominantly collagens. It typically leads to compromise of organ function and subsequent organ failure, and it is estimated that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res 20(14) 3637–43. ©2014 AACR.
Publisher: Cold Spring Harbor Laboratory
Date: 03-05-2019
DOI: 10.1101/624890
Abstract: Both luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal–like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including epithelial-to-mesenchymal transition (EMT), hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our high-resolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires an aberrant post-lactation developmental program that involves both cancer cells and cells from the TME, to shift molecular subtype and promote tumour progression, with potential to explain the increased risk and poor prognosis of breast cancer associated to childbirth.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428153.V1
Abstract: SLC7A11 multivariate survival analysis parameters.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2022
DOI: 10.1038/S41467-022-32255-7
Abstract: The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
Publisher: EMBO
Date: 13-08-2020
Publisher: MDPI AG
Date: 27-01-2021
Abstract: The lysyl oxidase (LOX) family of enzymes are a major driver in the biogenesis of desmoplastic matrix at the primary tumour and secondary metastatic sites. With the increasing interest in and development of anti-stromal therapies aimed at improving clinical outcomes of cancer patients, the Lox family has emerged as a potentially powerful clinical target. This review examines how lysyl oxidase family dysregulation in solid cancers contributes to disease progression and poor patient outcomes, as well as an evaluation of the preclinical landscape of LOX family targeting therapeutics. We also discuss the suitability of the LOX family as a diagnostic and/or prognostic marker in solid tumours.
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2020
DOI: 10.1101/2020.04.06.026963
Abstract: Differentiation of stem cells embedded within the mammary epithelium is orchestrated by lineage-specifying transcription factors. Unlike the well-defined luminal hierarchy, dissection of the basal lineage has been hindered by a lack of specific markers. Inhibitor of Differentiation 4 (ID4) is a basally-restricted helix-loop-helix (HLH) transcription factor essential for mammary development. Here we show that ID4 is highly expressed in basal stem cells and decreases during myoepithelial differentiation. By integrating transcriptomic, proteomic, and ChIP-sequencing data, we reveal that ID4 is required to suppress myoepithelial gene expression and cell fate. We identify the bHLH protein HEB as a direct binding partner of ID4, and describe a previously-unknown role for this regulator in mammary development. HEB binds to E-boxes in regulatory elements of developmental genes, negatively regulated by ID4, involved in extracellular matrix synthesis and cytoskeletal contraction. Together our findings support a model whereby ID4 binds to HEB and blocks it from promoting myoepithelial specialisation. These new insights expand our current understanding into control of myoepithelial differentiation and mammary gland morphogenesis.
Publisher: Public Library of Science (PLoS)
Date: 20-08-2008
Publisher: Springer Science and Business Media LLC
Date: 12-06-2017
DOI: 10.1038/NM.4352
Abstract: The extracellular matrix (ECM) is a master regulator of cellular phenotype and behavior. It has a crucial role in both normal tissue homeostasis and disease pathology. Here we present a fast and efficient approach to enhance the study of ECM composition and structure. Termed in situ decellularization of tissues (ISDoT), it allows whole organs to be decellularized, leaving native ECM architecture intact. These three-dimensional decellularized tissues can be studied using high-resolution fluorescence and second harmonic imaging, and can be used for quantitative proteomic interrogation of the ECM. Our method is superior to other methods tested in its ability to preserve the structural integrity of the ECM, facilitate high-resolution imaging and quantitatively detect ECM proteins. In particular, we performed high-resolution sub-micron imaging of matrix topography in normal tissue and over the course of primary tumor development and progression to metastasis in mice, providing the first detailed imaging of the metastatic niche. These data show that cancer-driven ECM remodeling is organ specific, and that it is accompanied by comprehensive changes in ECM composition and topological structure. We also describe differing patterns of basement-membrane organization surrounding different types of blood vessels in healthy and diseased tissues. The ISDoT procedure allows for the study of native ECM structure under normal and pathological conditions in unprecedented detail.
Publisher: Wiley
Date: 08-2019
DOI: 10.1002/CNR2.1209
Publisher: Wiley
Date: 19-04-2018
DOI: 10.1111/BPH.14195
Publisher: Springer Science and Business Media LLC
Date: 17-05-2019
Publisher: Impact Journals, LLC
Date: 03-10-2017
Publisher: American Society for Cell Biology (ASCB)
Date: 10-2018
Abstract: Increased tissue stiffness is a classic characteristic of solid tumors. One of the major contributing factors is increased density of collagen fibers in the extracellular matrix (ECM). Here, we investigate how cancer cells biomechanically interact with and respond to the stiffness of the ECM. Probing the adaptability of cancer cells to altered ECM stiffness using optical tweezers–based microrheology and deformability cytometry, we find that only malignant cancer cells have the ability to adjust to collagen matrices of different densities. Employing microrheology on the biologically relevant spheroid invasion assay, we can furthermore demonstrate that, even within a cluster of cells of similar origin, there are differences in the intracellular biomechanical properties dependent on the cells’ invasive behavior. We reveal a consistent increase of viscosity in cancer cells leading the invasion into the collagen matrices in comparison with cancer cells following in the stalk or remaining in the center of the spheroid. We hypothesize that this differential viscoelasticity might facilitate spheroid tip invasion through a dense matrix. These findings highlight the importance of the biomechanical interplay between cells and their microenvironment for tumor progression.
Publisher: Elsevier BV
Date: 09-2015
Publisher: No publisher found
Date: 2019
DOI: 10.1016/J.TRECAN.2019.09.010
Abstract: Cancer-associated fibroblasts (CAFs) are one of the most significant components in the tumour microenvironment (TME), where they can perform several protumourigenic functions. Several studies have recently reported that CAFs are more heterogenous and plastic than was previously thought. As such, there has been a shift in the field to study CAF subpopulations and the emergent functions of these subsets in tumourigenesis. In this review, we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC). We also discuss therapeutic approaches to selectively target protumourigenic CAF functions, while avoiding normal fibroblasts, providing insight into the future of stromal targeting for the treatment of PDAC and other solid tumours.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2017
DOI: 10.1038/S41598-017-00144-5
Abstract: The objective of this study was to evaluate the potential value of ultrasound (US) shear wave elastography (SWE) in assessing the relative change in elastic modulus in colorectal adenocarcinoma xenograft models in vivo and investigate any correlation with histological analysis. We sought to test whether non-invasive evaluation of tissue stiffness is indicative of pathological tumour changes and can be used to monitor therapeutic efficacy. US-SWE was performed in tumour xenografts in 15 NCr nude immunodeficient mice, which were treated with either the cytotoxic drug, Irinotecan, or saline as control. Ten tumours were imaged 48 hours post-treatment and five tumours were imaged for up to five times after treatment. All tumours were harvested for histological analysis and comparison with elasticity measurements. Elastic (Young's) modulus prior to treatment was correlated with tumour volume (r = 0.37, p = 0.008). Irinotecan administration caused significant delay in the tumour growth (p = 0.02) when compared to control, but no significant difference in elastic modulus was detected. Histological analysis revealed a significant correlation between tumour necrosis and elastic modulus (r = −0.73, p = 0.026). SWE measurement provided complimentary information to other imaging modalities and could indicate potential changes in the mechanical properties of tumours, which in turn could be related to the stages of tumour development.
Publisher: Portland Press Ltd.
Date: 22-11-2019
DOI: 10.1042/BST20190098
Abstract: The extracellular matrix (ECM) is a fundamental component of tissue microenvironments and its dysregulation has been implicated in a number of diseases, in particular cancer. Tumour desmoplasia (fibrosis) accompanies the progression of many solid cancers, and is also often induced as a result of many frontline chemotherapies. This has recently led to an increased interest in targeting the underlying processes. The major structural components of the ECM contributing to desmoplasia are the fibrillar collagens, whose key assembly mechanism is the enzymatic stabilisation of procollagen monomers by the lysyl oxidases. The lysyl oxidase family of copper-dependent amine oxidase enzymes are required for covalent cross-linking of collagen (as well as elastin) molecules into the mature ECM. This key step in the assembly of collagens is of particular interest in the cancer field since it is essential to the tumour desmoplastic response. LOX family members are dysregulated in many cancers and consequently the development of small molecule inhibitors targeting their enzymatic activity has been initiated by many groups. Development of specific small molecule inhibitors however has been hindered by the lack of crystal structures of the active sites, and therefore alternate indirect approaches to target LOX have also been explored. In this review, we introduce the importance of, and assembly steps of the ECM in the tumour desmoplastic response focussing on the role of the lysyl oxidases. We also discuss recent progress in targeting this family of enzymes as a potential therapeutic approach.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-03-2023
Abstract: Gene expression noise is known to promote stochastic drug resistance through the elevated expression of in idual genes in rare cancer cells. However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network. Furthermore, we reveal that the memory of this initially random state is retained following chemotherapy treatment across a series of in vitro, in vivo, and patient models. Using matched PDX models established at diagnosis and relapse from in idual patients, we show that HDAC inhibitor priming cannot erase the memory of this resistant state within relapsed neuroblastomas but improves response in the first-line setting by restoring drug-induced JNK activity within the chemoresistant population of treatment-naïve tumors.
Publisher: Portland Press Ltd.
Date: 06-10-2023
DOI: 10.1042/BST20230018
Publisher: eLife Sciences Publications, Ltd
Date: 09-07-2018
DOI: 10.7554/ELIFE.35800
Abstract: Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark Galene, a versatile multi-platform software tool for image-based correction of s le motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that Galene is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, Galene can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2012
DOI: 10.1038/NRC3319
Abstract: The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.
Publisher: Humana Press
Date: 2013
Publisher: Wiley
Date: 20-03-2017
Abstract: The proportion of adults in Australia meeting or exceeding the national guidelines for physical activity has remained relatively static over the past 10 years. The research objective was to measure self-reported physical activity and sedentary behaviour among ED patients in accordance with Australia's current physical activity and sedentary behaviour guidelines, revised in 2014. A convenience s le of participants was recruited from three EDs in Melbourne between February and May 2016. Eligible participants were administered the International Physical Activity Questionnaire - Short Form plus researcher-derived questions. Participants were assessed as whether meeting the physical activity guidelines or not, using pre-defined criteria. The proportion of 18-64 year olds meeting all of the physical activity guidelines was 19.0% (95% confidence interval [CI] 15.2-22.8). A majority of participants (63.1%, 95% CI 58.5-67.7) met the aerobic component of the guidelines although only 28.9% (95% CI 24.5-33.3) of participants reported undertaking strength building exercises two or more times per week. Adults in the oldest age group were found to be less likely to engage in muscle strengthening exercises (23.3%, n = 30) than those in the youngest age group (40.0%, n = 60, P = 0.005). Average daily sitting time (minutes) did not differ between men (median = 300) and women (median = 360, P = 0.118). Overall adherence with physical activity guidelines is low among adults attending the ED. All adults need to be encouraged to undertake muscle strengthening activities, especially adults in older age groups.
Publisher: Wiley
Date: 27-12-2017
Abstract: The nematode Caenorhabditis elegans is widely used as a model organism to study cell and developmental biology. Quantitative proteomics of C. elegans is still in its infancy and, so far, most studies have been performed on adult worm s les. Here, we used quantitative mass spectrometry to characterize protein level changes across the four larval developmental stages (L1-L4) of C. elegans. In total, we identified 4130 proteins, and quantified 1541 proteins that were present across all four stages in three biological replicates from independent experiments. Using hierarchical clustering and functional ontological analyses, we identified 21 clusters containing proteins with similar protein profiles across the four stages, and highlighted the most overrepresented biological functions in each of these protein clusters. In addition, we used the dataset to identify putative larval stage-specific proteins in each in idual developmental stage, as well as in the early and late developmental stages. In summary, this dataset provides system-wide analysis of protein level changes across the four C. elegans larval developmental stages, which serves as a useful resource for the C. elegans research community. MS data were deposited in ProteomeXchange (proteomecentral.proteomexchange.org) via the PRIDE partner repository with the primary accession identifier PXD006676.
Publisher: Springer International Publishing
Date: 2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-04-2017
DOI: 10.1126/SCITRANSLMED.AAI8504
Abstract: Fine-tuned manipulation of tumor tension and vasculature enhances response to chemotherapy and impairs metastatic spread in pancreatic cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2011
DOI: 10.1158/0008-5472.CAN-10-2868
Abstract: More than 90% of cancer patient mortality is attributed to metastasis. In this study, we investigated a role for the lysyl oxidase-related enzyme lysyl oxidase-like 2 (LOXL2) in breast cancer metastasis, in both patient s les and in vivo models. Analysis of a published microarray data set revealed that LOXL2 expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer. In immunocompetent or immunocompromised orthotopic and transgenic breast cancer models we showed that genetic, chemical or antibody-mediated inhibition of LOXL2 resulted in decreased metastasis. Mechanistic investigations revealed that LOXL2 promotes invasion by regulating the expression and activity of the extracellular proteins tissue inhibitor of metalloproteinase-1 (TIMP1) and matrix metalloproteinase-9 (MMP9). We found that LOXL2, TIMP1, and MMP9 are coexpressed during mammary gland involution, suggesting they function together in glandular remodeling after weaning. Finally, we found that LOXL2 is highly expressed in the basal/myoepithelial mammary cell lineage, like many other genes that are upregulated in basal-like breast cancers. Our findings highlight the importance of LOXL2 in breast cancer progression and support the development of anti-LOXL2 therapeutics for the treatment of metastatic breast cancer. Cancer Res 71(5) 1561–72. ©2011 AACR.
Publisher: The Company of Biologists
Date: 03-2011
DOI: 10.1242/DMM.004077
Abstract: Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.
Publisher: MDPI AG
Date: 22-05-2019
Abstract: Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2017
DOI: 10.1038/S41598-017-17177-5
Abstract: Organotypic co-cultures bridge the gap between standard two-dimensional culture and mouse models. Such assays increase the fidelity of pre-clinical studies, to better inform lead compound development and address the increasing attrition rates of lead compounds within the pharmaceutical industry, which are often a result of screening in less faithful two-dimensional models. Using large-scale acid-extraction techniques, we demonstrate a step-by-step process to isolate collagen I from commercially available animal byproducts. Using the well-established rat tail tendon collagen as a benchmark, we apply our novel kangaroo tail tendon collagen as an alternative collagen source for our screening-ready three-dimensional organotypic co-culture platform. Both collagen sources showed equal applicability for invasive, proliferative or survival assessment of well-established cancer models and clinically relevant patient-derived cancer cell lines. Additional readouts were also demonstrated when comparing these alternative collagen sources for stromal contributions to stiffness, organization and ultrastructure via atomic force microscopy, second harmonic generation imaging and scanning electron microscopy, among other vital biological readouts, where only minor differences were found between the preparations. Organotypic co-cultures represent an easy, affordable and scalable model to investigate drug responses within a physiologically relevant 3D platform.
Publisher: Oxford University Press (OUP)
Date: 31-01-2011
DOI: 10.1093/JNCI/DJQ569
Abstract: Emerging evidence implicates lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, in promoting metastasis of solid tumors. We investigated whether LOX plays an important role in the metastasis of colorectal cancer (CRC). We analyzed LOX expression in a patient CRC tissue microarray consisting of normal colon mucosa (n = 49), primary (n = 510), and metastatic (n = 198) tissues. LOX was overexpressed in CRC cell line SW480 (SW480+LOX), and the expression was knocked down in CRC cell line SW620 using LOX-specific short hairpin RNA (SW620+shLOX). Effect of LOX manipulation on three-dimensional cell proliferation and invasion was characterized in vitro. Effect of LOX manipulation on tumor proliferation and metastasis was investigated in a subcutaneous tumor mouse model (n = 3 mice per group) and in an intrasplenic metastatic mouse model (n = 3 mice per group). The mechanism of LOX-mediated effects via v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) was investigated using dasatinib, an inhibitor of SRC activation. All statistical tests were two-sided. Compared with normal colon tissue (n = 49), LOX expression was statistically significantly increased in tumor tissues (n = 510) of CRC patients (P < .001), and a greater increase was observed in metastatic tissue (n = 198). SW480+LOX cells showed a statistically significantly increased three-dimensional proliferation (P = .037) and invasion (P = .015), whereas SW620+shLOX cells showed reduced proliferation (P = .011) and invasion (P = .013) compared with controls. Subcutaneous tumor growth in mice was statistically significantly increased in SW480+LOX tumors (P = .036) and decreased in SW620+shLOX tumors (P = .048), and metastasis was statistically significantly increased in SW480+LOX tumors (P = .044) and decreased in SW620+shLOX tumors (SW620 control vs SW620+shLOX, mean = 1.0 luminescent signal, 95% confidence interval = 0.3 to 1.7 luminescent signal, vs mean = 0.3 luminescent signal, 95% confidence interval = 0.1 to 0.5 luminescent signal P = .035) compared with controls. LOX-mediated effects on tumor progression were associated with SRC activation, and these effects were inhibited by dasatinib. LOX showed an important role in CRC cell proliferation and metastasis and was dependent on the activation of SRC. These results have the potential to identify patients with high SRC activity, who may benefit from dasatinib treatment.
Publisher: BMJ
Date: 28-10-2017
DOI: 10.1136/GUTJNL-2017-315144
Abstract: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts ( specimens). Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428177
Abstract: Anti-proliferative effect of SLC7A11 knockdown in CAFs and the effect of SLC7A11 inhibition in MiaPaCa-2 PDAC cells and normal human pancreatic ductal epithelial (HPDE) cells.
Publisher: American Association for Cancer Research (AACR)
Date: 12-05-2021
DOI: 10.1158/0008-5472.CAN-20-2496
Abstract: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1053/J.GASTRO.2017.11.280
Abstract: Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment-specific therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428180
Abstract: Validation of SLC7A11 antibodies and SLC7A11 knockdown in CAFs and PDAC cells in vitro.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
DOI: 10.1038/S41467-019-10968-6
Abstract: Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.
Publisher: F1000 Research Ltd
Date: 10-09-2018
DOI: 10.12688/F1000RESEARCH.15064.2
Abstract: Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2020
DOI: 10.1038/S41598-020-69591-X
Abstract: Multifunctional nanocarriers (MNCs) promise to improve therapeutic outcomes by combining multiple classes of molecules into a single nanostructure, enhancing active targeting of therapeutic agents and facilitating new combination therapies. However, nanocarrier platforms currently approved for clinical use can still only carry a single therapeutic agent. The complexity and escalating costs associated with the synthesis of more complex MNCs have been major technological roadblocks in the pathway for clinical translation. Here, we show that plasma polymerized nanoparticles (PPNs), synthesised in reactive gas discharges, can bind and effectively deliver multiple therapeutic cargo in a facile and cost-effective process compatible with up scaled commercial production. Delivery of siRNA against vascular endothelial growth factor (siVEGF) at extremely low concentrations (0.04 nM), significantly reduced VEGF expression in hard-to-transfect cells when compared with commercial platforms carrying higher siRNA doses (6.25 nM). PPNs carrying a combination of siVEGF and standard of care Paclitaxel (PPN-Dual) at reduced doses ( 100 µg/kg) synergistically modulated the microenvironment of orthotopic breast tumors in mice, and significantly reduced tumor growth. We propose PPNs as a new nanomaterial for delivery of therapeutics, which can be easily functionalised in any laboratory setting without the need for additional wet-chemistry and purification steps.
Publisher: F1000 Research Ltd
Date: 08-2018
DOI: 10.12688/F1000RESEARCH.15064.1
Abstract: Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2017
DOI: 10.1038/NRC.2017.6
Abstract: It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2019
Publisher: Proceedings of the National Academy of Sciences
Date: 24-10-2022
Abstract: Organoid technology has provided unique insights into human organ development, function, and diseases. Patient-derived organoids are increasingly used for drug screening, modeling rare disorders, designing regenerative therapies, and understanding disease pathogenesis. However, the use of Matrigel to grow organoids represents a major challenge in the clinical translation of organoid technology. Matrigel is a poorly defined mixture of extracellular matrix proteins and growth factors extracted from the Engelbreth–Holm–Swarm mouse tumor. The extracellular matrix is a major driver of multiple cellular processes and differs significantly between tissues as well as in healthy and disease states of the same tissue. Therefore, we envisioned that the extracellular matrix derived from a native healthy tissue would be able to support organoid growth akin to organogenesis in vivo. Here, we have developed hydrogels from decellularized human and bovine endometrium. These hydrogels supported the growth of mouse and human endometrial organoids, which was comparable to Matrigel. Organoids grown in endometrial hydrogels were proteomically more similar to the native tissue than those cultured in Matrigel. Proteomic and Raman microspectroscopy analyses showed that the method of decellularization affects the biochemical composition of hydrogels and, subsequently, their ability to support organoid growth. The amount of laminin in hydrogels correlated with the number and shape of organoids. We also demonstrated the utility of endometrial hydrogels in developing solid scaffolds for supporting high-throughput, cell culture–based applications. In summary, endometrial hydrogels overcome a major limitation of organoid technology and greatly expand the applicability of organoids to understand endometrial biology and associated pathologies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428168.V1
Abstract: SLC7A11 knockdown in PDAC CAFs does not affect glutamate secretion and is maintained in the presence of oxidative stress.
No related grants have been discovered for Thomas Cox.