ORCID Profile
0000-0001-7603-0351
Current Organisation
Garvan Institute of Medical Research
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Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.IMMUNI.2014.11.012
Abstract: Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.
Publisher: eLife Sciences Publications, Ltd
Date: 27-06-2018
DOI: 10.7554/ELIFE.38847
Abstract: Drugs called bisphosphonates are used to treat a range of bone diseases, but how do they reach the enzymes that are their target?
Publisher: Wiley
Date: 27-06-2014
DOI: 10.1111/PCMR.12274
Abstract: Solid cancers are composed of heterogeneous zones containing proliferating and quiescent cells. Despite considerable insight into the molecular mechanisms underlying aberrant cell cycle progression, there is limited understanding of the relationship between the cell cycle on the one side, and melanoma cell motility, invasion, and drug sensitivity on the other side. Utilizing the fluorescent ubiquitination-based cell cycle indicator (FUCCI) to longitudinally monitor proliferation and migration of melanoma cells in 3D culture and in vivo, we found that invading melanoma cells cycle actively, while G1-arrested cells showed decreased invasion. Melanoma cells in a hypoxic environment or treated with mitogen-activated protein kinase pathway inhibitors remained G1-arrested for extended periods of time, with proliferation and invasion resuming after re-exposure to a more favorable environment. We challenge the idea that the invasive and proliferative capacity of melanoma cells are mutually exclusive and further demonstrate that a reversibly G1-arrested subpopulation survives in the presence of targeted therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2010
DOI: 10.1158/1535-7163.MCT-09-0894
Abstract: The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrow–derived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug. Mol Cancer Ther 9(5) 1408–18. ©2010 AACR.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.CEB.2014.05.002
Abstract: In the lymph node, T cells migrate rapidly and with striking versatility in a continuous scan for antigen presenting dendritic cells. The scanning process is greatly facilitated by the lymph node structure and composition. In vivo imaging has been instrumental in deciphering the spatiotemporal dynamics of intranodal T cell migration in both health and disease. Here we review recent developments in uncovering the migration modes employed by T cells in the lymph node, the underlying molecular mechanisms, and the scanning strategies utilised by T cells to ensure a timely response to antigenic stimuli.
Publisher: Wiley
Date: 06-2017
DOI: 10.1111/JNS.12208
Publisher: Elsevier BV
Date: 06-2010
Publisher: eLife Sciences Publications, Ltd
Date: 30-12-2021
DOI: 10.7554/ELIFE.72430
Abstract: Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1038/JID.2013.206
Abstract: Samaniego et al. (this issue) report on distinct tumor-associated mesenchymal cell (MC) populations in human melanomas. FAP(-)CD90(+) peritumoral MCs may be involved in immune cell recruitment from the bloodstream. FAP(+)CD90(-) intratumoral MCs were associated with extracellular matrix fiber deposition, and their numbers correlated with high immune cell infiltration. Thus, different MC subsets modulate the cellular composition of the intratumoral and peritumoral melanoma microenvironment.
Publisher: Elsevier BV
Date: 12-2006
Publisher: Wiley
Date: 2007
DOI: 10.1080/15216540701736285
Abstract: Multidrug resistance is a major obstacle to cancer treatment and leads to poor prognosis for the patient. Multidrug resistance-associated protein 1 (MRP1) transports a wide range of therapeutic agents as well as erse physiological substrates and may play a role in the development of drug resistance in several cancers including those of the lung, breast and prostate, as well as childhood neuroblastoma. The majority of patients with neuroblastoma present with widely disseminated disease at diagnosis and despite intensive treatment, the prognosis for such patients is dismal. There is increasing evidence that MRP1 is a MYCN target gene involved in the development of multidrug resistance in neuroblastoma. Given the importance of MRP1 overexpression in neuroblastoma, MRP1 inhibition may be a clinically relevant approach to improving patient outcome in this disease.
Publisher: Wiley
Date: 02-07-0006
DOI: 10.1111/BPH.12658
Publisher: Elsevier
Date: 2020
Publisher: Elsevier BV
Date: 07-2002
Publisher: Oxford University Press (OUP)
Date: 28-07-2011
DOI: 10.1093/JNCI/DJR256
Publisher: American Society for Clinical Investigation
Date: 03-10-2022
DOI: 10.1172/JCI160929
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.BCP.2014.05.023
Abstract: Multidrug resistance protein 4 (MRP4/ABCC4), a member of the ATP-binding cassette (ABC) transporter superfamily, is an organic anion transporter capable of effluxing a wide range of physiologically important signalling molecules and drugs. MRP4 has been proposed to contribute to numerous functions in both health and disease however, in most cases these links remain to be unequivocally established. A major limitation to understanding the physiological and pharmacological roles of MRP4 has been the absence of specific small molecule inhibitors, with the majority of established inhibitors also targeting other ABC transporter family members, or inhibiting the production, function or degradation of important MRP4 substrates. We therefore set out to identify more selective and well tolerated inhibitors of MRP4 that might be used to study the many proposed functions of this transporter. Using high-throughput screening, we identified two chemically distinct small molecules, Ceefourin 1 and Ceefourin 2, that inhibit transport of a broad range of MRP4 substrates, yet are highly selective for MRP4 over other ABC transporters, including P-glycoprotein (P-gp), ABCG2 (Breast Cancer Resistance Protein BCRP) and MRP1 (multidrug resistance protein 1 ABCC1). Both compounds are more potent MRP4 inhibitors in cellular assays than the most widely used inhibitor, MK-571, requiring lower concentrations to effect a comparable level of inhibition. Furthermore, Ceefourin 1 and Ceefourin 2 have low cellular toxicity, and high microsomal and acid stability. These newly identified inhibitors should be of great value for efforts to better understand the biological roles of MRP4, and may represent classes of compounds with therapeutic application.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Informa UK Limited
Date: 15-12-2007
DOI: 10.4161/CC.6.24.5021
Abstract: The cellular response to DNA damage is critical for maintenance of genomic integrity and inhibition of tumorigenesis. Mutations or aberrant expression of the E3 ubiquitin ligase EDD have been observed in a number of carcinomas and we recently reported that EDD modulates activity of the DNA damage checkpoint kinase, CHK2. Here, we demonstrate that EDD is necessary for G(1)/S and intra S phase DNA damage checkpoint activation and for the maintenance of G(2)/M arrest after double strand DNA breaks. Defective checkpoint activation in EDD-depleted cells led to radio-resistant DNA synthesis, premature entry into mitosis, accumulation of polyploid cells, and cell death via mitotic catastrophe. In addition to decreased CHK2 activation in EDD-depleted cells, the expression of several key cell cycle mediators including Cdc25A/C and E2F1 was altered, suggesting that these checkpoint defects may be both CHK2-dependent and -independent. These data support a role for EDD in the maintenance of genomic stability, emphasising the potential importance of dysregulated EDD expression and/or function in the evolution of cancer.
Publisher: eLife Sciences Publications, Ltd
Date: 10-11-2021
Publisher: Frontiers Media SA
Date: 14-08-2019
Publisher: Elsevier BV
Date: 2016
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2022
DOI: 10.1101/2022.02.28.480959
Abstract: Mevalonate kinase deficiency (MKD) is caused by biallelic loss-of-function mutations in MVK , leading to recurrent fevers and systemic inflammation. We describe new mouse avatars of MKD bearing p.Val377Ile (the commonest variant) or deletions in Mvk . Compound heterozygous mice recapitulated the biochemical phenotype of MKD, with build-up of unprenylated GTPases and increased plasma mevalonic acid. Mice with different deficiencies in mevalonate kinase revealed new insights into the genotype-phenotype relationship and mirrored the variability in the prenylation defect in human MKD, with p.V377I homozygous mice having a milder phenotype than compound heterozygous animals. The inflammatory response to LPS was enhanced in compound heterozygous mice in vivo and elevated serum interleukin-1β was abrogated by NLRP3 inflammasome inhibition. Increased temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and defective prenylation in vitro and in vivo , highlighting increased body temperature as a likely trigger of inflammatory flares and an additional potential target for future therapeutic approaches.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Cold Spring Harbor Laboratory
Date: 10-08-2021
DOI: 10.1101/2021.08.09.455652
Abstract: Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently-labelled bisphosphonate is internalised by alveolar macrophages and peritoneal macrophages in vivo . Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
Location: Australia
Location: Venezuela (Bolivarian Republic of)
Location: Venezuela (Bolivarian Republic of)
No related grants have been discovered for Marcia Munoz.