A5041788878- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Adenosine and Purinergic Signaling
- interferon and immune responses
- Cancer-related Molecular Pathways
- Cancer Research and Treatments
- NF-κB Signaling Pathways
- Immune cells in cancer
- Immune Cell Function and Interaction
- RNA Interference and Gene Delivery
- Cancer, Lipids, and Metabolism
- Occupational and environmental lung diseases
- Receptor Mechanisms and Signaling
- Cancer therapeutics and mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- DNA Repair Mechanisms
- Inflammation biomarkers and pathways
- Phagocytosis and Immune Regulation
- Peptidase Inhibition and Analysis
- Molecular Biology Techniques and Applications
- Cytokine Signaling Pathways and Interactions
- Genetics and Neurodevelopmental Disorders
- Toxoplasma gondii Research Studies
CRUK Lung Cancer Centre of Excellence
2013-2024
University College London
2013-2024
Massachusetts Institute of Technology
2022
Spanish National Cancer Research Centre
2022
Dana-Farber Cancer Institute
2022
Harvard University
2022
Cancer Institute (WIA)
2017
Imperial College London
2014
University of Salerno
2011-2012
Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, SHARPIN, the only known ligase that generates linkages. HOIP catalytically active LUBAC component. Here, we show both constitutive Tie2-Cre-driven deletion lead to aberrant endothelial cell death, resulting in defective vascularization embryonic lethality at midgestation. Ablation tumor necrosis factor receptor 1 (TNFR1) prevents defects, death...
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether to what extent signaling cells affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant FADD dependent identify TRAIL-induced secretome drive monocyte polarization myeloid-derived suppressor (MDSCs)...
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many cancer cells without causing toxicity vivo. However, to date, TRAIL-receptor agonists have only shown limited therapeutic benefit clinical trials. This can, most likely, be attributed the fact that 50% of all cell lines and primary human cancers are TRAIL resistant. Consequently, future TRAIL-based therapies will require addition sensitizing agents remove crucial blocks pathway. Here, we identify...
The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion HOIP or (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic pharmacological evidence the lethal HoipE-KO Hoil-1E-KO mice caused TNFR1-induced, caspase-8-mediated apoptosis occurs independently kinase activity RIPK1. In...
Abstract CD73 is a cell surface enzyme that suppresses T cell-mediated immune responses by producing extracellular adenosine. Growing evidence suggests targeting in cancer may be useful for an effective therapeutic outcome. In this study, we demonstrate administration of specific inhibitor, adenosine 5′-(α,β-methylene)diphosphate (APCP), to melanoma-bearing mice induced significant tumor regression promoting the release Th1- and Th17-associated cytokines microenvironment. CD8+ cells were...
CpG-oligodeoxynucleotide (CpG-ODN; CpG), a Toll-like receptor-9 ligand, has been widely studied as potential antitumor adjuvant. is highly expressed on lung carcinoma tissues and some immune cells, such plasmacytoid dendritic cells B cells.The aim of our study was to elucidate the effect CpG in mouse model carcinoma.C57Bl/6j, cell-deficient, Nude mice were intravenously implanted with metastatic B16-F10 melanoma killed 3 7 days after administration.Administration increased tumor growth...
Abstract The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized this process might also or contribute to inflammatory disease lung failure following SARS-CoV-2 infection. To test hypothesis, developed a novel mouse-adapted model (MA20) recapitulates key pathological features of COVID-19. Concomitantly with...
Abstract Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance first-line therapy alternative therapies are urgently required overcome this resistance. In study, we tested the efficacy dinaciclib, an FDA-orphan drug inhibitor cyclin-dependent kinase (CDK) 9, among other CDKs, SCLC. Furthermore, report on a newly...
Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines the discovery subset defined by loss function nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association observed across human early passage cultures, mouse xenografts tumour explants. We BAP1 activity...
Cl-IB-MECA, synthetic A3 adenosine receptor agonist, is a potential anticancer agent. In this study, we have examined the effect of Cl-IB-MECA in mouse melanoma model. significantly inhibited tumor growth immune-competent mice. Notably, number tumor-infiltrating NK1.1+ cells and CD8+ T was increased Cl-IB-MECA-treated This correlated with high levels necrosis factor α (TNF-α) interferon γ tissue. Depletion either or completely abrogated antitumor Cl-IB-MECA. Accordingly, did not affect nude...
Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays crucial role in limiting tumor progression. In mice, administration enhances the anti-tumor T cell-mediated response. However, little known about activity of on CD8+ cells. The aim this study was to investigate effect ex vivo treatment cells, adoptively transferred melanoma-bearing mice. Adoptive transfer Cl-IB-MECA-treated cells or single (20 ng/mouse) inhibited growth compared with control group and significantly improved...
Significance Many new cancer drugs fail at the clinical stage owing to poor efficacy and/or excessive toxicity, though whether this reflects shortcomings of target or drug is often unclear. To gain earlier insights into factors that can influence therapeutic index inhibition in vivo, we combine inducible RNA interference and somatic engineering technologies produce a cost-effective platform enables systemic suppression candidate normal tissues tumor cells same mouse. By comparing...
Abstract Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance apoptosis has long been thought contribute resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from broad range cancers, importantly without inducing detectable adverse events. Remarkably, combination with was also highly on cancers resistant both, standard-of-care chemotherapy various targeted therapeutic approaches. Dynamic...
Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically kill cancer cells in vivo. On the basis of this, TRAIL-receptor (TRAIL-R) agonists were devised for clinical use. However, date, TRAIL-R have only limited therapeutic benefit trials. This can most likely be attributed fact that primary human cancers are TRAIL resistant. It is therefore important identify potent and cancer-selective TRAIL-sensitizers overcome resistance. Recently,...