A5085111107- Cancer, Hypoxia, and Metabolism
- Angiogenesis and VEGF in Cancer
- Cell Adhesion Molecules Research
- Cellular transport and secretion
- Protease and Inhibitor Mechanisms
- Caveolin-1 and cellular processes
- Axon Guidance and Neuronal Signaling
- Cellular Mechanics and Interactions
- Peptidase Inhibition and Analysis
- Amino Acid Enzymes and Metabolism
- Cancer Cells and Metastasis
- Fibroblast Growth Factor Research
- Metabolism, Diabetes, and Cancer
- Cancer Research and Treatments
- Liver physiology and pathology
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Protein Kinase Regulation and GTPase Signaling
- Kruppel-like factors research
- 14-3-3 protein interactions
- Cancer Treatment and Pharmacology
- Lymphatic System and Diseases
- Microtubule and mitosis dynamics
- Pancreatic function and diabetes
- Protein Hydrolysis and Bioactive Peptides
University of Sheffield
2016-2025
Cancer Research UK Scotland Institute
2011-2017
University of Glasgow
2017
Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
2007-2012
Technion – Israel Institute of Technology
2012
Breast tumours are embedded in a collagen I-rich extracellular matrix (ECM) network, where nutrients scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for cancer cells endure these conditions. Here, we demonstrated that the presence of ECM supported growth invasive breast cells, but not non-transformed mammary epithelial under amino acid starvation, through mechanism macropinocytosis-dependent uptake. Importantly, showed this behaviour was acquired...
Inhibition of αvβ3 integrin or expression oncogenic mutants p53 promote invasive cell migration by enhancing endosomal recycling α5β1 under control the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase α (DGK-α), which phosphorylates to phosphatidic acid (PA), was required for RCP be mobilized and tethered at tips pseudopods allow RCP-dependent resulting invasiveness tumor cells. Expression a constitutive-active mutant DGK-α drove invasion in...
Integrin trafficking is key to cell migration, but little known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 undergoes tensin-dependent centripetal movement from periphery populate adhesions located under nucleus. From here, ligand-engaged integrins are internalized control Arf subfamily GTPase, Arf4, and trafficked nearby late endosomes/lysosomes. Suppression or Arf4-dependent endocytosis disrupts flow ligand-bound endosomes/lysosomes their...
Chloride intracellular channel 3 (CLIC3) drives invasiveness of pancreatic and ovarian cancer by acting in concert with Rab25 to regulate recycling α5β1 from late endosomes the plasma membrane. Here we show that two estrogen receptor (ER)-negative breast cell lines CLIC3 has little influence on integrin recycling, but controls trafficking pro-invasive matrix metalloprotease, MT1-MMP. In MDA-MB-231 cells MT1-MMP are localised primarily endosomal/lysosomal compartments located above plane...
Abstract Neuropilin-1 (NRP1) is a coreceptor for multiple extracellular ligands. NRP1 widely expressed in cancer cells and advanced human tumors; however, its functional relevance signaling mechanisms are unclear. Here, we show that expression controls viability proliferation of different cells, independent short intracellular tail. We found the domain interacts with EGF receptor (EGFR) promotes cascade elicited upon or TGF-α stimulation. Upon silencing, ability ligand-bound EGFR to cluster...
Abstract The role of glutaminolysis in providing metabolites to support tumour growth is well-established, but the involvement glutamine metabolism invasive processes yet be elucidated. Here we show that normal mammary epithelial cells consume glutamine, do not secrete glutamate. Indeed, low levels extracellular glutamate are necessary maintain homoeostasis, and provision drives disruption morphology promotes key characteristics phenotype such as lumen-filling basement membrane disruption....
Macropinocytosis (MP), the actin-dependent bulk uptake of extracellular fluids, plays a central role in nutrient scavenging, allowing cancer cells to sustain their growth hypoxic and nutrient-deprived microenvironment often found solid tumours. The lack soluble nutrients several oncogenic signalling pathways, with RAS being most studied, push MP-dependent internalisation proteins, which are then digested lysosomes, replenishing intracellular pools. This review will highlight recent advances...
Diacylglycerol kinases (DGKs) convert diacylglycerol (DAG) into phosphatidic acid (PA), acting as molecular switches between DAG- and PA-mediated signaling. We previously showed that Src-dependent activation plasma membrane recruitment of DGKα are required for growth-factor-induced cell migration ruffling, through the control Rac small-GTPase localization. Herein we unveil a signaling pathway which coordinates localization Rac. show upon hepatocyte growth-factor stimulation, DGKα, by...
Abstract The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis vivo unclear. Here we identify an RTK of the Eph family, EphA2, be a cargo RCP-regulated endocytic pathway which controls cell:cell repulsion . Phosphorylation at Ser 435 Lemur kinase-3 (LMTK3) EphA2 897 Akt are both necessary Rab14-dependent (and Rab11-independent) trafficking...
Ovarian cancer is the 3rd most common gynaecological malignancy worldwide, with a 5‐year survival rate of < 30% in presence metastasis. Metastatic progression characterised by extensive remodelling extracellular matrix, primarily mediated secreted proteases, including members ‘a disintegrin and metalloprotease thrombospondin motif’ (ADAMTS) family. In particular, ADAMTS5 has been reported to be upregulated ovarian malignant tumours compared borderline benign lesions, suggesting it might...
Abstract Pancreatic cancers have a poorly vascularized and nutrient-deficient microenvironment making them more susceptible to nutrient deprivation. Evidence has shown that Ductal Adenocarcinoma (PDAC) cells survive in nutrient-deprived hypovascular microenvironment. Here, we investigate the roles of Extracellular Matrix (ECM) supporting growth PDAC different nutrient-deprivation conditions. Our cell proliferation, microscopy targeted Mass Spectroscopy metabolomics data showed Matrigel, but...
Diacylglycerol kinases (DGKs) metabolize diacylglycerol to phosphatidic acid. In T lymphocytes, DGKα acts as a negative regulator of TCR signaling by decreasing levels and inducing anergy. this study, we show that upon costimulation the with CD28 or lymphocyte activation molecule (SLAM), DGKα, but not DGKζ, exits from nucleus undergoes rapid regulation its enzymatic activity. Inhibition is dependent on expression SAP, an adaptor protein mutated in X-linked lymphoproliferative disease, which...
Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling invasion recruiting atypical PKC at ruffling sites promoting RCP-mediated recycling α5β1 integrin to the tip pseudopods. In here we investigate signaling pathway which mediates SDF-1α-induced MDA-MB-231 invasive breast...
Diacylglycerol kinases (Dgk) phosphorylate diacylglycerol (DG) to phosphatidic acid (PA), thus turning off and on, respectively, DG-mediated PA-mediated signaling pathways. We previously showed that hepatocyte growth factor (HGF), vascular endothelial factor, anaplastic lymphoma kinase activate Dgkα in leukemia cells through a Src-mediated mechanism activation of is required for chemotactic, proliferative, angiogenic vitro. Here, we investigate the downstream events pathways regulated by...
The interaction between cancer cells and the extracellular matrix (ECM) plays a pivotal role in tumour progression. While degradation of ECM proteins has been well characterised, endocytosis its impact on cell progression, migration metastasis is poorly understood. internalisation increased invasive breast cells, suggesting it may support invasiveness. Here we developed high-content screening assay to study uptake. We identified that mitogen-activated protein kinase (MAPK) family members,...
Abstract Nutrient stress accompanies several stages of tumor progression, including metastasis formation. Metabolic reprogramming is a hallmark cancer, and it has been associated with tolerance anchorage-independent cell survival. Adaptive responses are required to support cancer survival under these conditions. In this issue Cancer Research, Nam colleagues showed that the extracellular matrix (ECM) receptor integrin β3 was upregulated in lung cells response nutrient starvation, resulting...