ORCID Profile
0000-0001-6360-1952
Current Organisation
Beatson Institute for Cancer Research
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Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.CEB.2016.04.003
Abstract: Chemotaxis is a fundamentally important part of biology, but we know very little about how gradients of chemoattractant are formed. One answer is self-generated gradients, in which the moving cells break down the attractant to provide their own gradient as they migrate. Here we discuss where self-generated gradients are known, how they can be recognized, and where they are likely to be found in the future.
Publisher: Wiley
Date: 09-11-2012
DOI: 10.1111/TAN.12014
Abstract: Granzymes (Grz) are a family of serine proteases found in the granules of cytotoxic lymphocytes and are emerging as an important group of proteins involved in immune function and surveillance. Grz have both cytotoxic and more recently reported non-cytotoxic roles, however these functions are still subject to thorough investigation. The significance of the cytotoxic and importantly the non-cytotoxic roles of Grz will be discussed in this review, detailing accepted and controversial functions.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2008
Abstract: Human GraB (hGraB) preferentially induces apoptosis via Bcl-2-regulated mitochondrial damage but can also directly cleave caspases and caspase substrates in cell-free systems. How hGraB kills cells when it is delivered by cytotoxic lymphocytes (CL) and the contribution of hGraB to CL-induced death is still not clear. We show that primary human natural killer (hNK) cells, which specifically used hGraB to induce target cell death, were able to induce apoptosis of cells whose mitochondria were protected by Bcl-2. Purified hGraB also induced apoptosis of Bcl-2-overexpressing targets but only when delivered at 5- to 10-fold the concentration required to kill cells expressing endogenous Bcl-2. Caspases were critical in this process as inhibition of caspase activity permitted clonogenic survival of Bcl-2-overexpressing cells treated with hGraB or hNK cells but did not protect cells that only expressed endogenous Bcl-2. Our data therefore show that hGraB triggers caspase activation via mitochondria-dependent and mitochondria-independent mechanisms that are activated in a hierarchical manner, and that the combined effects of Bcl-2 and direct caspase inhibition can block cell death induced by hGraB and primary hNK cells.
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3480-5_17
Abstract: We describe three chemotaxis assays-Insall chambers, circular invasion assays, and 3D organotypic assays-that are particularly appropriate for measuring migration of cancer cells in response to gradients of soluble attractants. Each assay has defined advantages, and together they provide the best possible quantitative assessment of cancer chemotaxis.
Publisher: American Society of Hematology
Date: 12-02-2009
Publisher: Public Library of Science (PLoS)
Date: 14-10-2014
Publisher: Springer Science and Business Media LLC
Date: 24-01-2014
DOI: 10.1038/CDD.2013.203
Publisher: Springer Science and Business Media LLC
Date: 07-06-2013
DOI: 10.1038/CDD.2013.59
Publisher: Springer Science and Business Media LLC
Date: 11-11-2021
DOI: 10.1038/S41467-021-26849-W
Abstract: Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.IMMUNI.2011.04.007
Abstract: Cytotoxic lymphocyte-mediated apoptosis is dependent on the delivery of perforin to secretory granules and its ability to form calcium-dependent pores in the target cell after granule exocytosis. It is unclear how cytotoxic lymphocytes synthesize and store perforin without incurring damage or death. We discovered that the extreme C terminus of perforin was essential for rapid trafficking from the endoplasmic reticulum to the Golgi compartment. Substitution of the C-terminal tryptophan residue resulted in retention of perforin in the ER followed by calcium-dependent toxic activity that eliminated host cells. We also found that N-linked glycosylation of perforin was critical for transport from the Golgi to secretory granules. Overall, an intact C terminus and N-linked glycosylation provide accurate and efficient export of perforin from the endoplasmic reticulum to the secretory granules and are critical for cytotoxic lymphocyte survival.
Publisher: The Company of Biologists
Date: 2017
DOI: 10.1242/JCS.207514
Abstract: Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then also migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency. Knockdown of the lipid phosphatase LPP3 - but not its homologues LPP1 or LPP2 - diminishes the cell's ability to break down LPA. This is specific for chemotactically active LPAs, such as the 18:1 and 20:4 species. Inhibition of autotaxin-mediated LPA production does not diminish outward chemotaxis, but loss of LPP3-mediated LPA breakdown blocks it. Similarly, in both 2D and 3D invasion assays, knockdown of LPP3 diminishes melanoma cells' ability to invade. Our results demonstrate that LPP3 is the key enzyme in melanoma cells’ breakdown of LPA, and confirm the importance of attractant breakdown in LPA-mediated cell steering.
Publisher: American Society of Hematology
Date: 04-04-2013
DOI: 10.1182/BLOOD-2012-07-446146
Abstract: Granzymes diffuse through perforin pores on the target cell plasma membrane.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Olivia Susanto.