ORCID Profile
0000-0002-2347-7835
Current Organisation
University of Technology Sydney
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Microbial genetics | Synthetic biology | Genetics | Genomics
Publisher: MDPI AG
Date: 29-03-2023
DOI: 10.3390/MI14040751
Abstract: This paper describes, in detail, a method that uses flow cytometry to quantitatively characterise the performance of continuous-flow microfluidic devices designed to separate particles. Whilst simple, this approach overcomes many of the issues with the current commonly utilised methods (high-speed fluorescent imaging, or cell counting via either a hemocytometer or a cell counter), as it can accurately assess device performance even in complex, high concentration mixtures in a way that was previously not possible. Uniquely, this approach takes advantage of pulse processing in flow cytometry to allow quantitation of cell separation efficiencies and resulting s le purities on both single cells as well as cell clusters (such as circulating tumour cell (CTC) clusters). Furthermore, it can readily be combined with cell surface phenotyping to measure separation efficiencies and purities in complex cell mixtures. This method will facilitate the rapid development of a raft of continuous flow microfluidic devices, will be helpful in testing novel separation devices for biologically relevant clusters of cells such as CTC clusters, and will provide a quantitative assessment of device performance in complex s les, which was previously impossible.
Publisher: Oxford University Press (OUP)
Date: 27-09-2011
DOI: 10.1002/STEM.706
Abstract: Recent characterization of mammary stem and progenitor cells has improved our understanding of the transcriptional network that coordinates mammary development however, little is known about the mechanisms that enforce lineage commitment and prevent transdifferentiation in the mammary gland. The E-twenty six transcription factor Elf5 forces the differentiation of mammary luminal progenitor cells to establish the milk producing alveolar lineage. Methylation of the Elf5 promoter has been proposed to act as a lineage gatekeeper during embryonic development. We used bisulphite sequencing to investigate in detail whether Elf5 promoter methylation plays a role in lineage commitment during mammary development. An increase in Elf5 expression was associated with decreasing Elf5 promoter methylation in differentiating HC11 mammary cells. Similarly, purified mammary epithelial cells from mice had increased Elf5 expression and decreased promoter methylation during pregnancy. Finally, analysis of epithelial subpopulations revealed that the Elf5 promoter is methylated and silenced in the basal, stem cell-containing population relative to luminal cells. These results demonstrate that Elf5 promoter methylation is lineage-specific and developmentally regulated in the mammary gland in vivo, and suggest that loss of Elf5 methylation specifies the mammary luminal lineage, while continued Elf5 methylation maintains the stem cell and myoepithelial lineages.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Oxford University Press (OUP)
Date: 10-05-2011
Abstract: The p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway is an important regulator of cell processes, whose deregulation leads to the development and progression of cancer. Defining the role of each p38MAPK family member in these processes has been difficult. To date, most studies of the p38MAPK pathways focused on function of the p38α isoform, which is widely considered to negatively regulate malignant transformation nonetheless, few reports address the p38γ and p38δ isoforms. Here, we used embryonic fibroblasts derived from mice lacking p38γ or p38δ and show evidence that these isoforms participate in several processes involved in malignant transformation. We observed that lack of either p38γ or p38δ increased cell migration and metalloproteinase-2 secretion, whereas only p38δ deficiency impaired cell contact inhibition. In addition, lack of p38γ in K-Ras-transformed fibroblasts led to increased cell proliferation as well as tumorigenesis both in vitro and in vivo. Our results indicate that p38γ and p38δ have a role in the suppression of tumor development.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.BIOCEL.2008.01.013
Abstract: Choline kinase alpha (ChoKalpha) is an enzyme involved in the metabolism of phospholipids recently found to play a relevant role in the regulation of cell proliferation, oncogenic transformation and human carcinogenesis. In addition, this novel oncogene has been recently defined as a prognostic factor in human cancer, and as a promising target for therapy since its specific inhibitors display efficient antitumoral activity in vivo. However, the mechanism by which this enzyme is involved in the regulation of these processes is not yet understood. Using differential microarray analysis, we identify target genes that provide the basis for the understanding of the molecular mechanism for the regulation of cell proliferation and transformation mediated by over-expression of the human ChoKalpha. These results fully support a critical role of this enzyme in the regulation of the G1-->S transition at different levels, and its relevant role in human carcinogenesis. The molecular basis to understand the connection between phospholipids metabolism and cell cycle regulation through choline kinase is reported.
Publisher: Public Library of Science (PLoS)
Date: 12-11-2009
Publisher: Rockefeller University Press
Date: 24-02-2023
DOI: 10.1084/JEM.20220610
Abstract: Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
Publisher: Public Library of Science (PLoS)
Date: 30-12-2015
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2013
DOI: 10.1158/0008-5472.CAN-12-1472
Abstract: Basal breast cancer cells feature high expression of the Src family kinase Lyn that has been implicated in the pathogenicity of this disease. In this study, we identified novel Lyn kinase substrates, the most prominent of which was the atypical kinase SgK269 (PEAK1). In breast cancer cells, SgK269 expression associated with the basal phenotype. In primary breast tumors, SgK269 overexpression was detected in a subset of basal, HER2-positive, and luminal cancers. In immortalized MCF-10A mammary epithelial cells, SgK269 promoted transition to a mesenchymal phenotype and increased cell motility and invasion. Growth of MCF-10A acini in three-dimensional (3D) culture was enhanced upon SgK269 overexpression, which induced an abnormal, multilobular acinar morphology and promoted extracellular signal–regulated kinase (Erk) and Stat3 activation. SgK269 Y635F, mutated at a major Lyn phosphorylation site, did not enhance acinar size or cellular invasion. We show that Y635 represents a Grb2-binding site that promotes both Stat3 and Erk activation in 3D culture. RNA interference–mediated attenuation of SgK269 in basal breast cancer cells promoted acquisition of epithelial characteristics and decreased anchorage-independent growth. Together, our results define a novel signaling pathway in basal breast cancer involving Lyn and SgK269 that offers clinical opportunities for therapeutic intervention. Cancer Res 73(6) 1969–80. ©2012 AACR.
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1038/S41523-019-0127-5
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.
Publisher: Frontiers Media SA
Date: 30-11-2021
Abstract: Over 90% of potential anti-cancer drug candidates results in translational failures in clinical trials. The main reason for this failure can be attributed to the non-accurate pre-clinical models that are being currently used for drug development and in personalised therapies. To ensure that the assessment of drug efficacy and their mechanism of action have clinical translatability, the complexity of the tumor microenvironment needs to be properly modelled. 3D culture models are emerging as a powerful research tool that recapitulates in vivo characteristics. Technological advancements in this field show promising application in improving drug discovery, pre-clinical validation, and precision medicine. In this review, we discuss the significance of the tumor microenvironment and its impact on therapy success, the current developments of 3D culture, and the opportunities that advancements that in vitro technologies can provide to improve cancer therapeutics.
Publisher: Wiley
Date: 03-10-2022
DOI: 10.1002/CYTO.A.24504
Abstract: Sensitive and quantitative detection of molecular biomarkers is crucial for the early diagnosis of diseases like metabolic syndrome and cancer. Here we present a single‐molecule sandwich immunoassay by imaging the number of single nanoparticles to diagnose aggressive prostate cancer. Our assay employed the photo‐stable upconversion nanoparticles (UCNPs) as labels to detect the four types of circulating antigens in blood circulation, including glypican‐1 (GPC‐1), leptin, osteopontin (OPN), and vascular endothelial growth factor (VEGF), as their serum concentrations indicate aggressive prostate cancer. Under a wide‐field microscope, a single UCNP doped with thousands of lanthanide ions can emit sufficiently bright anti‐Stokes' luminescence to become quantitatively detectable. By counting every single streptavidin‐functionalized UCNP which specifically labeled on each sandwich immune complex across multiple fields of views, we achieved the Limit of Detection (LOD) of 0.0123 ng/ml, 0.2711 ng/ml, 0.1238 ng/ml, and 0.0158 ng/ml for GPC‐1, leptin, OPN and VEGF, respectively. The serum circulating level of GPC‐1, leptin, OPN, and VEGF in a mixture of 10 healthy normal human serum was 25.17 ng/ml, 18.04 ng/ml, 11.34 ng/ml, and 1.55 ng/ml, which was within the assay dynamic detection range for each analyte. Moreover, a 20% increase of GPC‐1 and OPN was observed by spiking the normal human serum with recombinant antigens to confirm the accuracy of the assay. We observed no cross‐reactivity among the four biomarker analytes, which eliminates the false positives and enhances the detection accuracy. The developed single upconversion nanoparticle‐assisted single‐molecule assay suggests its potential in clinical usage for prostate cancer detection by monitoring tiny concentration differences in a panel of serum biomarkers.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2018
Publisher: Springer Science and Business Media LLC
Date: 07-11-2017
DOI: 10.1038/S41467-017-01393-8
Abstract: Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers. H2A.Zac nucleosome occupancy is rapidly remodeled to flank the AR sites to initiate the formation of nucleosome-free regions and the production of AR-enhancer RNAs upon androgen treatment. Remarkably higher levels of global H2A.Zac correlate with poorer prognosis. Altogether these data demonstrate the novel contribution of H2A.Zac in activation of newly formed enhancers in prostate cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633199.V1
Abstract: Neutrophil interactions with LLC cells in unmanipulated and treated tumors.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2022
DOI: 10.1186/S13058-022-01525-Z
Abstract: The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N -ethyl- N -nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 ( Oas2 ), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice. To determine if sole activation of Oas2 could alter the course of mammary cancer, we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan–Meier survival analysis with immunohistochemistry and flow cytometry. Oas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when the Oas2 mutation was present. These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1245/S10434-008-0166-X
Abstract: TWIST1 is a basic helix-loop-helix (bHLH) transcription factor that has been involved in tumor progression and metastasis in several cancer types, although no evidence has been provided yet on its implication in colorectal carcinogenesis. We examined the expression pattern of TWIST1 messenger RNA (mRNA) in 54 colorectal cancer biopsies compared with each respective adjacent normal mucosa by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) methodology. TWIST1 mRNA was found significantly overexpressed in colorectal cancer s les compared to nontumorous colon mucosa (P < 0.0001). Receiver operating characteristic (ROC) curve analysis demonstrated that TWIST1 mRNA levels are significantly increased in patients with nodal invasion and, interestingly, a significant correlation with patient sex was also found. Evidence for upregulation of TWIST1 mRNA in colorectal cancer is provided, suggesting its implication in the onset of malignant progression of this disease. In addition, significant higher levels of TWIST1 mRNA were found in men than in women, suggesting a possible transcriptional regulation of TWIST1 by sexual hormones. The use of TWIST1 as a new prognostic marker of advanced malignancy, and as a potential therapeutic target in colorectal cancer, is proposed.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 02-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8LC00403J
Abstract: Rapid and reliable capture and analysis of single cells in a chemically isolated static droplet array for fast-tracking single cell discoveries.
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.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2023
DOI: 10.1101/2023.04.04.535585
Abstract: Single-cell transcriptomics has emerged as the preferred tool to define cell identity through the analysis of gene expression signatures. However, there are limited studies that have comprehensively compared the performance of different scRNAseq systems in complex tissues. Here, we present a systematic comparison of three well-established high throughput 3’-scRNAseq platforms: Drop-seq, 10x Chromium and BD Rhapsody using tumours that present high cell ersity. Our experimental design includes both fresh and artificially damaged s les from the same tumours, which also provides a comparable dataset to examine their performance under challenging conditions. The performance metrics used in this study consist of gene sensitivity, mitochondrial content, reproducibility, clustering capabilities, cell type representation and ambient RNA contamination. These analyses showed that BD Rhapsody and 10x Chromium have similar but higher gene sensitivity than Drop-seq, while BD Rhapsody has the highest mitochondrial content. Interestingly, we found cell type detection biases between platforms, including a lower proportion of endothelial and myofibroblast cells in BD Rhapsody and lower gene sensitivity in granulocytes for 10x Chromium. Moreover, the source of the ambient noise was different between plate-based and droplet-based platforms. In conclusion, our reported platform differential performance should be considered for the selection of the scRNAseq method during the study experimental designs.
Publisher: American Society for Clinical Investigation
Date: 03-10-2022
DOI: 10.1172/JCI165107
Publisher: American Association for Cancer Research (AACR)
Date: 14-02-2023
DOI: 10.1158/0008-5472.CAN-21-4025
Abstract: Intratumoral injection of microbial bioparticles stimulates neutrophil antitumor functions, suggesting pathways for optimizing efficacy of microbial therapies and paving the way for their broader utilization in the clinic.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2012
DOI: 10.1038/ONC.2012.271
Abstract: Grb2-associated binder 1 (Gab1) is a docking protein that transduces signals from a variety of tyrosine kinases, including Met and the epidermal growth factor receptor (EGFR). Although the related protein Gab2 is strongly implicated in human cancer, a role for Gab1 has been less clear. However, a screen for gene mutations in breast cancer identified two somatic mutations in Gab1, Y83C and T387N. In this paper we describe the functional characterization of these Gab1 mutants. MCF-10A immortalized mammary epithelial cells overexpressing Gab1 Y83C and T387N exhibited a more elongated, fibroblastic phenotype compared with wild-type Gab1 controls. Expression of Gab1 or the mutants promoted epidermal growth factor (EGF)-independent proliferation in monolayer culture to a similar degree. However, in Matrigel culture, both mutants enhanced the formation of acini exhibiting an aberrant, branched morphology. In addition, expression of the mutants modestly increased Erk activation. The two mutants also enhanced branching morphogenesis in a different mammary epithelial cell line, HC11. To gain further insights into the mechanism of action of these mutations, we mapped Gab1 phosphorylation sites by mass spectrometry. This detected phosphorylation of T387 but not Y83. Cellular stimulation with EGF or hepatocyte growth factor (HGF) led to a transient, or sustained, induction of T387 phosphorylation, respectively. As T387 corresponds in position to Gab2 T391, which suppresses Gab2 signaling in a phosphorylation-dependent manner, these data support a model in which the T387N mutation abrogates negative-feedback regulation of Gab1. Interrogation of publically-available databases revealed additional cancer-associated mutations at, or in close proximity to, identified serine/threonine phosphorylation sites in other docking proteins. These data indicate that aberrant Gab1 signaling can directly contribute to breast cancer progression, and that negative feedback sites in docking proteins can be targeted by oncogenic mutations.
Publisher: Elsevier BV
Date: 03-2023
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633184.V1
Abstract: Characterization of neutrophil populations in single cell analysis.
Publisher: Elsevier BV
Date: 10-2007
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.CELREP.2017.09.022
Abstract: The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.ADVENZREG.2010.09.010
Abstract: We have summarized here the importance of ChoKα1 in human carcinogenesis. ChoKα1 displays its oncogenic activity through activation of specific signaling pathways that influence on cell proliferation and survival. It is overexpressed in a large number of human tumors with an incidence of 40-60% of all tumors investigated. Currently, there is an active effort in the development of strategies to knockdown the activity of ChoKα through specific siRNA or small molecules inhibitors. Results from genetic silencing or from treatment with MN58b, a well characterized ChoKα inhibitor showing antiproliferative and antitumoral effect in mice xenografts, provide strong support to this concept, indicating that the design of new antitumoral drugs must be selective against this isoform. However, affecting the other two known isoforms of ChoK may have also therapeutic consequences since the physiologically active form of ChoK may be constituted by homo or heterodimers. Furthermore, alteration of the ChoKβ activity might lead to a change in the lipid content of the cells of particular tissues such as skeletal muscle as described in the ChoKβ null mice (Sher et al., 2006). Finally, the identification of the ChoKα1 isoform as an excellent novel tool for the diagnosis and prognosis of cancer patients may have clinical consequences of immediate usefulness. On one hand, the use of specific monoclonal antibodies against ChoKα1 as a tool for diagnosis in paraffin embedded s les from patient biopsies, through standard immunohistochemistry techniques, can now be achieved (Gallego-Ortega et al., 2006). On the other hand, it has been recently described the prognostic value of determination of ChoKα1 expression levels in non-small cell lung cancer using real time quantitative PCR technology (Ramírez de Molina et al., 2007). Therefore, further research should be supported on the utility of ChoK isoforms as a promising area to improve cancer diagnosis and treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633202
Abstract: Neutrophil migration before and after microbial bioparticle treatment.
Publisher: Public Library of Science (PLoS)
Date: 02-01-2020
Publisher: Elsevier BV
Date: 2016
Publisher: Impact Journals, LLC
Date: 03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 07-2005
DOI: 10.1158/0008-5472.CAN-04-4416
Abstract: Choline kinase is overexpressed in human breast, lung, colorectal, and prostate tumors, a finding that suggests the involvement of this enzyme in carcinogenesis. Here we show that overexpression of choline kinase induce oncogenic transformation of human embryo kidney fibroblasts and canine epithelial Madin-Darby canine kidney cells. Choline kinase lays downstream of RhoA signaling and is activated through ROCK kinase, one of the best-characterized RhoA effectors. In keeping with this, coexpression of RhoA and choline kinase potentiates both anchorage independent growth and tumorigenesis. Finally, choline kinase–mediated transformation is sensitive to MN58b, a well-characterized specific choline kinase inhibitor. These results provide the definitive evidence that choline kinase has oncogenic properties and that choline kinase inhibition constitutes a novel valid antitumor strategy.
Publisher: American Society for Clinical Investigation
Date: 04-2022
DOI: 10.1172/JCI148667
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9LC00872A
Abstract: Gradient-sized spheroids can be simultaneously generated on a single chip using a liquid-dome method assisted by the surface tension. The facile method can be used for investigation of the size-dependent behaviors of spheroids in biomedical research.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633202.V1
Abstract: Neutrophil migration before and after microbial bioparticle treatment.
Publisher: Research Square Platform LLC
Date: 05-07-2022
DOI: 10.21203/RS.3.RS-1789675/V1
Abstract: Backgound: Exercise following a breast cancer diagnosis is known to improve outcomes. In multiple pre-clinical cancer models, exercise alone has shown to inhibit tumour growth. One of the suggested mechanisms for this benefit include exercise-induced recruitment and activation of anti-cancer immune cells. In this study, we aimed to investigate the effects of exercise on breast cancer tumour growth, the tumour immune microenvironment and tumour vasculature in vivo. Methods A triple negative breast cancer patient derived xenograft (PDX) in immunocopromised hosts and a transgenic MMTV-PyMT mouse mammary tumor model in immunocompetent hosts were used for this study. Mice were randomised to either exercise (running wheels) or sedentary controls (locked wheels), and tumour volume and survival measured. Tumours were harvested for immune cell and vascular changes, as well as cytokine analysis by immunohistochemistry and multiplex analysis respectively. Results Exercise improved median overall survival relative to controls in the PDX model (84 vs 33 days, p = 0.02), but did not affect tumour growth or survival in the MMTV-PyMT model. Proliferation (Ki67) and apoptosis (cleaved caspase 3) did not differ between the intervention arms in the PDX model. In contrast, apoptosis was significantly higher with exercise in the MMTV-PyMT model (p = 0.05). Exercise did not affect the extent of tumour vasculature or immune cell infiltration in the two models, but increased Th1-type cytokines such as INF-γ (p 0.05) in the PDX model and reduced INF-γ (p 0.001) in the MMTV-PyMT model compared with controls, in the absence of accelerated tumour growth. Conclusion Exercise-induced modulation of Th1-type cytokines was associated with median overall survival in the PDX model. In contrast, tumour growth was not impacted by exercise and no immunological changes were found in the immunocompetent MMTV-PyMT model.
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2020
DOI: 10.1101/2020.10.30.356774
Abstract: Cancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression 1,2 . However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression.
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2021
DOI: 10.1101/2021.10.25.465657
Abstract: Emerging single-cell technologies provide high-resolution measurements of distinct cellular modalities opening new avenues for generating detailed cellular atlases of many and erse tissues. The high dimensionality, sparsity, and inaccuracy of single cell sequencing measurements, however, can obscure discriminatory information, mask cellular subtype variations and complicate downstream analyses which can limit our understanding of cell function and tissue heterogeneity. Here, we present a novel pre-processing method (scPSD) inspired by power spectral density analysis that enhances the accuracy for cell subtype separation from large-scale single-cell omics data. We comprehensively benchmarked our method on a wide range of single-cell RNA-sequencing datasets and showed that scPSD pre-processing, while being fast and scalable, significantly reduces data complexity, enhances cell-type separation, and enables rare cell identification. Additionally, we applied scPSD to transcriptomics and chromatin accessibility cell atlases and demonstrated its capacity to discriminate over 100 cell types across the whole organism and across different modalities of single-cell omics data.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633196
Abstract: Neutrophils engage in multiple interactions with LLC tumor cells following microbial bioparticle treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633187.V1
Abstract: SUPPLEMENTARY FIGURES 1-10 SUPPLEMENTARY TABLE and VIDEO LEGENDS EXTENDED MATERIALS AND METHODS
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: 14-04-2023
DOI: 10.1158/0008-5472.C.6599657.V1
Abstract: Abstract The inflammatory microenvironment of solid tumors creates a protumorigenic milieu that resembles chronic inflammation akin to a subverted wound healing response. Here, we investigated the effect of converting the tumor microenvironment from a chronically inflamed state to one of acute microbial inflammation by injecting microbial bioparticles directly into tumors. Intratumoral microbial bioparticle injection led to rapid and dramatic changes in the tumor immune composition, the most striking of which was a substantial increase in the presence of activated neutrophils. i In situ /i photoconversion and intravital microscopy indicated that tumor neutrophils transiently switched from sessile producers of VEGF to highly motile neutrophils that clustered to make neutrophil-rich domains in the tumor. The neutrophil clusters remodeled tumor tissue and repressed tumor growth. Single-cell transcriptional analysis of microbe-stimulated neutrophils showed a profound shift in gene expression towards heightened activation and antimicrobial effector function. Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8 sup + /sup T-cell recruitment. Microbial therapy also boosted CD8 sup + /sup T-cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumor-bearing mice and provided protection in a model of tumor recurrence. These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumor neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers. Significance: Intratumoral injection of microbial bioparticles stimulates neutrophil antitumor functions, suggesting pathways for optimizing efficacy of microbial therapies and paving the way for their broader utilization in the clinic. /
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633199
Abstract: Neutrophil interactions with LLC cells in unmanipulated and treated tumors.
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: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633193
Abstract: Neutrophil interactions with LLC cells lead to tumor cell blebbing.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633193.V1
Abstract: Neutrophil interactions with LLC cells lead to tumor cell blebbing.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8LC01239C
Abstract: A step-by-step guide for droplet-based single cell RNAseq experiments, practical considerations and technical notes.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2021
DOI: 10.1038/S41590-021-01067-0
Abstract: The signals driving the adaptation of type 2 dendritic cells (DC2s) to erse peripheral environments remain mostly undefined. We show that differentiation of CD11b
Publisher: Springer Science and Business Media LLC
Date: 18-11-2019
DOI: 10.1038/S41388-019-1091-0
Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC.
Publisher: Bioscientifica
Date: 07-2017
DOI: 10.1530/ERC-16-0404E
Publisher: Informa UK Limited
Date: 21-12-2018
Publisher: Public Library of Science (PLoS)
Date: 27-12-2012
Publisher: Wiley
Date: 05-09-2020
DOI: 10.1002/CYTO.A.24209
Abstract: In the past few years, the rapid development of single‐cell analysis techniques has allowed for increasingly in‐depth analysis of DNA, RNA, protein, and epigenetic states, at the level of the in idual cell. This unprecedented characterization ability has been enabled through the combination of cytometry, microfluidics, genomics, and informatics. Although traditionally discrete, when properly integrated, these fields create the synergistic field of Genomic Cytometry. In this review, we look at the in idual methods that together gave rise to the broad field of Genomic Cytometry. We further outline the basic concepts that drive the field and provide a framework to understand this increasingly complex, technology‐intensive space. Thus, we introduce Genomic Cytometry as an emerging field and propose that synergistic rationalization of disparate modalities of cytometry, microfluidics, genomics, and informatics under one banner will enable massive leaps forward in the understanding of complex biology. © 2020 International Society for Advancement of Cytometry
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1535-7163.MCT-13-0012
Abstract: Overexpression of the antiapoptotic factor BCL-2 is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumors, provided a stronger predictor of patient survival (P = 0.019) when compared with gene expression (n = 522). In multiple cell models of acquired endocrine resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to antimitotic agents: nocodazole, paclitaxel, and the PLK1 inhibitor BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next-generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with nonresectable, metastatic disease. Mol Cancer Ther 12(9) 1874–85. ©2013 AACR.
Publisher: Frontiers Media SA
Date: 12-11-2018
Publisher: American Thoracic Society
Date: 15-09-2022
Publisher: Public Library of Science (PLoS)
Date: 08-11-2017
Publisher: Bioscientifica
Date: 04-2017
DOI: 10.1530/ERC-16-0404
Abstract: A cancer cell-centric view has long dominated the field of cancer biology. Research efforts have focussed on aberrant cancer cell signalling pathways and on changes to cancer cell DNA. Mounting evidence demonstrates that many cancer-associated cell types within the tumour stroma co-evolve and support tumour growth and development, greatly modifying cancer cell behaviour, facilitating invasion and metastasis and controlling dormancy and sensitivity to drug therapy. Thus, these stromal cells represent potential targets for cancer therapy. Among these cell types, immune cells have emerged as a promising target for therapy. The adaptive and the innate immune system play an important role in normal mammary development and breast cancer. The number of infiltrating adaptive immune system cells with tumour-rejecting capacity, primarily, T lymphocytes, is lower in breast cancer compared with other cancer types, but infiltration occurs in a large proportion of cases. There is strong evidence demonstrating the importance of the immunosuppressive role of the innate immune system during breast cancer progression. A consideration of components of both the innate and the adaptive immune system is essential for the design and development of immunotherapies in breast cancer. In this review, we focus on the importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) as potential targets for breast cancer therapy.
Publisher: Oxford University Press (OUP)
Date: 25-05-2022
DOI: 10.1093/NAR/GKAC436
Abstract: Emerging single-cell technologies provide high-resolution measurements of distinct cellular modalities opening new avenues for generating detailed cellular atlases of many and erse tissues. The high dimensionality, sparsity, and inaccuracy of single cell sequencing measurements, however, can obscure discriminatory information, mask cellular subtype variations and complicate downstream analyses which can limit our understanding of cell function and tissue heterogeneity. Here, we present a novel pre-processing method (scPSD) inspired by power spectral density analysis that enhances the accuracy for cell subtype separation from large-scale single-cell omics data. We comprehensively benchmarked our method on a wide range of single-cell RNA-sequencing datasets and showed that scPSD pre-processing, while being fast and scalable, significantly reduces data complexity, enhances cell-type separation, and enables rare cell identification. Additionally, we applied scPSD to transcriptomics and chromatin accessibility cell atlases and demonstrated its capacity to discriminate over 100 cell types across the whole organism and across different modalities of single-cell omics data.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2018
DOI: 10.1038/S41467-018-07497-Z
Abstract: Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1 Cre Robo2 F/F ) show increased activation of Robo1 + myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1 Cre Robo2 F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2 low ROBO1 high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633187
Abstract: SUPPLEMENTARY FIGURES 1-10 SUPPLEMENTARY TABLE and VIDEO LEGENDS EXTENDED MATERIALS AND METHODS
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.C.6599657
Abstract: Abstract The inflammatory microenvironment of solid tumors creates a protumorigenic milieu that resembles chronic inflammation akin to a subverted wound healing response. Here, we investigated the effect of converting the tumor microenvironment from a chronically inflamed state to one of acute microbial inflammation by injecting microbial bioparticles directly into tumors. Intratumoral microbial bioparticle injection led to rapid and dramatic changes in the tumor immune composition, the most striking of which was a substantial increase in the presence of activated neutrophils. i In situ /i photoconversion and intravital microscopy indicated that tumor neutrophils transiently switched from sessile producers of VEGF to highly motile neutrophils that clustered to make neutrophil-rich domains in the tumor. The neutrophil clusters remodeled tumor tissue and repressed tumor growth. Single-cell transcriptional analysis of microbe-stimulated neutrophils showed a profound shift in gene expression towards heightened activation and antimicrobial effector function. Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8 sup + /sup T-cell recruitment. Microbial therapy also boosted CD8 sup + /sup T-cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumor-bearing mice and provided protection in a model of tumor recurrence. These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumor neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers. Significance: Intratumoral injection of microbial bioparticles stimulates neutrophil antitumor functions, suggesting pathways for optimizing efficacy of microbial therapies and paving the way for their broader utilization in the clinic. /
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633184
Abstract: Characterization of neutrophil populations in single cell analysis.
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: Springer Science and Business Media LLC
Date: 16-11-2017
DOI: 10.1038/S41598-017-15885-6
Abstract: Quantification of cellular antigens and their interactions via antibody-based detection methods are widely used in scientific research. Accurate high-throughput quantitation of these assays using general image analysis software can be time consuming and challenging, particularly when attempted by users with limited image processing and analysis knowledge. To overcome this, we have designed Andy’s Algorithms, a series of automated image analysis pipelines for FIJI, that permits rapid, accurate and reproducible batch-processing of 3,3 ′ -diaminobenzidine (DAB) immunohistochemistry, proximity ligation assays (PLAs) and other common assays. Andy’s Algorithms incorporates a step-by-step tutorial and optimization pipeline to make batch image analysis simple for the untrained user and adaptable across laboratories. Andy’s algorithms provide a simpler, faster, standardized work flow compared to existing programs, while offering equivalent performance and additional features, in a free to use open-source application of FIJI. Andy’s Algorithms are available at GitHub, publicly accessed at ndlaw1841/Andy-s-Algorithm .
Publisher: Springer Science and Business Media LLC
Date: 27-03-2015
DOI: 10.1038/NCOMMS7548
Abstract: Basal-like breast cancer (BLBC) is a heterogeneous disease with poor prognosis however, its cellular origins and aetiology are poorly understood. In this study, we show that inhibitor of differentiation 4 (ID4) is a key regulator of mammary stem cell self-renewal and marks a subset of BLBC with a putative mammary basal cell of origin. Using an ID4GFP knock-in reporter mouse and single-cell transcriptomics, we show that ID4 marks a stem cell-enriched subset of the mammary basal cell population. ID4 maintains the mammary stem cell pool by suppressing key factors required for luminal differentiation. Furthermore, ID4 is specifically expressed by a subset of human BLBC that possess a very poor prognosis and a transcriptional signature similar to a mammary stem cell. These studies identify ID4 as a mammary stem cell regulator, deconvolute the heterogeneity of BLBC and link a subset of mammary stem cells to the aetiology of BLBC.
Publisher: Future Medicine Ltd
Date: 11-2013
DOI: 10.2217/BMT.13.50
Abstract: SUMMARY The ETS transcription factor ELF5 specifies the formation of the secretory cell lineage of the mammary gland during pregnancy, by directing cell fate decisions of the mammary progenitor cells. The decision-making activity continues in breast cancer, where in luminal breast cancer cells forced ELF5 expression suppresses estrogen sensitivity and shifts gene expression toward the basal molecular subtype. The development of anti-estrogen resistance in luminal breast cancer is accompanied by increased expression of ELF5 and acquired dependence on ELF5 for continued proliferation, providing a potential new therapeutic target or prognostic marker to improve the treatment of this stage of the disease. Forced ELF5 expression suppresses the mesenchymal phenotype, making cells more epithelial and producing lower rates of invasion and motility. Conversely, loss of ELF5 promotes metastasis, with a clear corollary in the claudin-low subtype of breast cancer, which does not express ELF5 and is highly metastatic, or during the final stages of tumor progression, where loss of ELF5 expression may be involved in the acquisition of the lethal phenotype. In circumstances where ELF5 expression increases in parallel with metastatic potential, such as anti-estrogen resistant luminal breast cancers and basal breast cancer, there is much more to be understood about ELF5 and metastasis.
Publisher: MDPI AG
Date: 27-02-2020
DOI: 10.3390/CELLS9030561
Abstract: The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.
Publisher: The Company of Biologists
Date: 04-2013
DOI: 10.1242/DEV.088948
Abstract: Progesterone-RankL paracrine signaling has been proposed as a driver of stem cell expansion in the mammary gland, and Elf5 is essential for the differentiation of mammary epithelial progenitor cells. We demonstrate that Elf5 expression is induced by progesterone and that Elf5 and progesterone cooperate to promote alveolar development. The progesterone receptor and Elf5 are expressed in a mutually exclusive pattern, and we identify RankL as the paracrine mediator of the effects of progesterone on Elf5 expression in CD61+ progenitor cells and their consequent differentiation. Blockade of RankL action prevented progesterone-induced side branching and the expansion of Elf5+ mature luminal cells. These findings describe a mechanism by which steroid hormones can produce the expansion of steroid hormone receptor-negative mammary epithelial cells.
Publisher: Wiley
Date: 08-09-2021
Abstract: Mammary tumor organoids have become a promising in vitro model for drug screening and personalized medicine. However, the dependency on the basement membrane extract (BME) as the growth matrices limits their comprehensive application. In this work, mouse mammary tumor organoids are established by encapsulating tumor pieces in non‐adhesive alginate. High‐throughput generation of organoids in alginate microbeads is achieved utilizing microfluidic droplet technology. Tumor pieces within the alginate microbeads developed both luminal‐ and solid‐like structures and displayed a high similarity to the original fresh tumor in cellular phenotypes and lineages. The mechanical forces of the luminal organoids in the alginate capsules are analyzed with the theory of the thick‐wall pressure vessel (TWPV) model. The luminal pressure of the organoids increase with the lumen growth and can reach 2 kPa after two weeks’ culture. Finally, the mammary tumor organoids are treated with doxorubicin and latrunculin A to evaluate their application as a drug screening platform. It is found that the drug response is related to the luminal size and pressures of organoids. This high‐throughput culture for mammary tumor organoids may present a promising tool for preclinical drug target validation and personalized medicine.
Publisher: Springer Science and Business Media LLC
Date: 31-07-2014
Publisher: Springer Science and Business Media LLC
Date: 07-01-2016
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633196.V1
Abstract: Neutrophils engage in multiple interactions with LLC tumor cells following microbial bioparticle treatment.
Start Date: 2023
End Date: 12-2023
Amount: $682,792.00
Funder: Australian Research Council
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