A5062746446- Melanoma and MAPK Pathways
- Ocular Oncology and Treatments
- Protein Degradation and Inhibitors
- Cell Adhesion Molecules Research
- Ubiquitin and proteasome pathways
- Retinal Development and Disorders
- Microtubule and mitosis dynamics
- Cancer Mechanisms and Therapy
- Cellular Mechanics and Interactions
- Nanoplatforms for cancer theranostics
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Computational Drug Discovery Methods
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Inflammasome and immune disorders
- RNA regulation and disease
- Atherosclerosis and Cardiovascular Diseases
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Cancer Immunotherapy and Biomarkers
- Urticaria and Related Conditions
- Hippo pathway signaling and YAP/TAZ
- HER2/EGFR in Cancer Research
- Advanced biosensing and bioanalysis techniques
Thomas Jefferson University
2015-2024
Sidney Kimmel Cancer Center
2015-2024
Albany Medical Center Hospital
2002-2023
Durham University
2023
Thomas Jefferson University Hospital
2022
Melanoma Institute Australia
2016
Jefferson College
2012
University of North Carolina at Chapel Hill
1997-2004
Indiana University School of Medicine
1999-2001
Psychiatry Research Trust
1997
Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis forming pores in plasma membrane. Here we show that also permeabilizes mitochondrial membrane, releasing cytochrome c and activating apoptosome. Cytochrome release activation response to intrinsic extrinsic apoptotic stimuli are significantly reduced GSDME-deficient cells comparing with wild type cells. GSDME deficiency accelerates cell growth culture a mouse model of melanoma....
Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N
Combinations of BRAF inhibitors and MEK (BRAFi + MEKi) are FDA-approved to treat V600E/K-mutant melanoma. Efficacy BRAFi MEKi associates with cancer cell death alterations in the tumor immune microenvironment; however, links poorly understood. We show that caused durable melanoma regression an immune-mediated manner. treatment promoted cleavage gasdermin E (GSDME) release HMGB1, markers pyroptotic death. GSDME-deficient showed defective HMGB1 release, reduced tumor-associated T activated...
Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and impact of altered redox microenvironment on immunologic reaction to tumors is limited.We isolated exosomes from ovarian cancer through ultracentrifuge characterized by Western-blots Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, 3D live cell imaging were used study interactions between cells, macrophages CD3 T vitro. The role exosomal miR-155-5p growth was...
Integrin-mediated cell adhesion causes activation of MAP kinases and increased tyrosine phosphorylation focal kinase (FAK). Autophosphorylation FAK leads to the binding SH2-domain proteins including Src-family Grb2-Sos complex. Since is a key regulator Ras signal transduction pathway, one plausible hypothesis has been that integrin-mediated cascade ultimately mitogen activated protein (MAP) activation. Thus, in this scenario would serve as an upstream activity. However, report we present...
Recent studies have demonstrated that the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10), antagonist of phosphosphoinositol-3-kinase (PI3K) signaling cascade, is susceptible to H2O2-dependent oxidative inactivation. This study describes use redox-engineered cell lines identify as sensitive inactivation by mitochondrial H2O2. Increases in steady state production derived H2O2, a result manganese superoxide dismutase (Sod2) overexpression, led oxidation was...
Integrin-mediated adhesion to the extracellular matrix permits efficient growth factor-mediated activation of signal–regulated kinases (ERKs). Points regulation have been localized level receptor phosphorylation or downstream components, Raf and MEK (mitogen-activated protein kinase/ERK kinase). However, it is also well established that ERK translocation from cytoplasm nucleus required for G1 phase cell cycle progression. Here we show nuclear substrate, Elk-1 at serine 383, anchorage...
Abstract: The two pathological lesions found in the brains of Alzheimer's disease patients, neurofibrillary tangles and neuritic plaques, are likely to be formed through a common pathway. Neurofibrillary intracellular aggregates paired helical filaments, main component which is hyperphosphorylated forms microtubule‐associated protein τ. Extracellular plaques diffuse vascular amyloid deposits β‐amyloid protein, 4‐kDa derived from precursor (APP). Using conditions vitro under proline‐directed...
Abstract We evaluated the role of cytoskeletal elements in degradation endogenous proteins via autophgy using biochemical and morphological techniques. In absence exogenous amino acids, was enhanced cultured normal rat kidney cells. This degradative state accompanied by a 4‐fold increase occurrence autophagic vacuoles. presence drugs that induce depolymerization microfilaments (cytochalasins B D) or microtubules (nocodazole), protein not nutrient‐deprived Although these had similar...
Melanoma cells are highly resistant to anoikis, a form of apoptosis induced in nonadherent/inappropriate adhesion conditions. Depleting B-RAF or the prosurvival Bcl-2 family protein Mcl-1 renders mutant melanoma susceptible anoikis. In this study, we examined effect targeting on survival primary stage cultured three-dimensional type I collagen gels, which partially mimics dermal microenvironment. Depletion/inhibition with small interfering RNA inhibitor, PLX4720, collagen. Apoptosis was...
Abstract Tumor cells often use developmental processes to progress toward advanced disease. The E-box transcription factor TWIST1 is essential epithelial–mesenchymal transition (EMT) and cell migration in the developing neural crest. In melanoma, which derives from crest lineage, enhanced expression has been linked worse clinical prognosis. However, mechanisms underlying whether aberrant levels promote steps melanoma progression remain unknown. Here, we report that elevated mRNA/protein...
Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification this heterogeneous cancer, several targeted immune therapies were approved increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) live tissue samples from 384 patients representing the full spectrum clinical, therapeutic, mutational, heterogeneity melanoma. PDX been...
Abstract Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to liver, leaving patients with few options. Recurrent activating mutations G proteins, Gαq Gα11, are observed approximately 93% of all uveal melanomas. Although therapeutic intervention downstream Gαq/11 targets has been unsuccessful treating melanoma, we have found that inhibitor, FR900359 (FR), effectively inhibits oncogenic signaling cells expressing either mutant or Gα11. Inhibition by FR...
Uveal melanoma is the most common eye cancer in adults. Approximately 50% of patients with uveal develop metastatic (mUM) liver, even after successful treatment primary lesions. mUM refractory to current chemo- and immune-therapies, die within a year. characterized by gain-of-function mutations
Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation metastatic microenvironments resistance therapies. Mechanisms underlying tumor cell remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads invasive properties, including the expression mesenchymal genes extracellular matrix, promotes tolerance BRAF and/or MEK inhibitors. We...
Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were required to achieve cytotoxic effect of DC661. Inhibition cathepsins, or iron calcium chelation, did rescue DC661-induced cytotoxicity. PPT1 induced lysosomal lipid peroxidation (LLP), which led membrane permeabilization...
ABSTRACT Integrin-mediated anchorage of NIH3T3 fibroblasts to the extracellular matrix component fibronectin permits efficient growth factor signaling p42 and p44 forms mitogen-activated protein kinase (MAPK). Since integrins bridge focal adhesion sites actin cytoskeleton, we analyzed role these integrin-associated structures in activation p44-MAPKs. Use specific reagents that disrupt stress fiber formation demonstrated upon readhesion cells fibronectin, were poorly spread lacked prominent...