A5062386392- Colorectal Cancer Treatments and Studies
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Cell Adhesion Molecules Research
- Angiogenesis and VEGF in Cancer
- Proteoglycans and glycosaminoglycans research
- Cellular Mechanics and Interactions
- Colorectal Cancer Surgical Treatments
- Fibroblast Growth Factor Research
- Protease and Inhibitor Mechanisms
- Gastric Cancer Management and Outcomes
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Myofascial pain diagnosis and treatment
- Musculoskeletal pain and rehabilitation
- Collagen: Extraction and Characterization
- Lymphatic System and Diseases
- 3D Printing in Biomedical Research
- Cancer Cells and Metastasis
- S100 Proteins and Annexins
- Signaling Pathways in Disease
- Monoclonal and Polyclonal Antibodies Research
- Kruppel-like factors research
- Cinema and Media Studies
- Mesenchymal stem cell research
- Galectins and Cancer Biology
Loughborough University
2022-2023
ETH Zurich
2009-2021
Paul Scherrer Institute
2017-2018
Charles Humbert 8
2014
Boston University
2006-2010
Bio-oriented Technology Research Advancement Institution
2010
Regulation of angiogenesis involves interactions between vascular endothelial growth factor (VEGF) and components the extracellular matrix, including fibronectin heparan sulfate. In present study, we identified two classes VEGF binding sites on fibronectin. One was constitutively available whereas availability other modulated by conformational state Atomic force microscopy studies revealed that heparin hydrophilic substrates promoted extended conformation fibronectin, leading to increased...
We investigated the mechanism by which heparin enhances binding of vascular endothelial growth factor (VEGF) to extracellular matrix protein fibronectin. In contrast other systems, where acts as a scaffold, we found that functions catalytically modulate VEGF site availability on By measuring and surface-immobilized fibronectin, show substoichiometric amounts exposed cryptic sites within fibronectin remain available after removal. Measurement association dissociation kinetics for indicated...
Platelet-derived growth factor (PDGF) signaling is essential for processes involving cell motility and differentiation during embryonic development in a wide variety of organisms including the mouse, frog, zebrafish, sea urchin. In early Xenopus laevis embryos, PDGF-AA provides guidance cues migration anterior mesendoderm cells as they move across fibronectin-rich extracellular matrix. The long form PDGF-A includes positively charged carboxyl-terminal retention motif that can interact with...
Purpose: Despite the wide use of antiangiogenic drugs in clinical setting, predictive biomarkers response to these are still unknown.Experimental Design: We applied whole-exome sequencing matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance standard treatment regimens, including inhibitors VEGF:VEGFR2 pathway. performed extensive functional experiments, ectopic expression VEGFR2 mutants...
Pro-lysyl oxidase is secreted as a 50-kDa proenzyme and then cleaved to 30-kDa mature enzyme (lysyl (LOX)) an 18-kDa propeptide (LOX-PP)). The presence of LOX-PP in the cell layers phenotypically normal osteoblast cultures led us investigate effects on differentiation. Data indicate that inhibits terminal mineralization primary calvaria when added at early stages differentiation, with no seen present later stages. was found inhibit serum- FGF-2-stimulated DNA synthesis growth. Enzyme-linked...
Since evidence is rising that extracellular matrix (ECM) fibers might serve as reservoirs for growth factors and cytokines, we investigated the interaction between fibronectin (FN) interleukin-7 (IL-7), a cytokine of immunological significance target several immunotherapies. By employing FN fiber stretch assay Förster resonance energy transfer (FRET) confocal microscopy, found stretching increased IL-7 binding. We localized binding site on CD loop IL-7, since synthetic peptide also bound...
An increasing body of evidence suggests important roles extracellular matrix (ECM) in regulating stem cell fate. This knowledge can be exploited tissue engineering applications for the design ECM scaffolds appropriate to direct differentiation. By probing conformation fibronectin (Fn) using fluorescence resonance energy transfer (FRET), we show here that heparin treatment fibroblast-derived resulted more extended conformations fibrillar Fn ECM. Since is a highly negatively charged molecule...
A large number of extracellular matrix proteins have been found in phosphorylated states, yet little is known about how the phosphorylation might affect cell functions. We thus tested hypothesis whether fibronectin, a major adhesion protein, affects behavior. Controlled vitro fibronectin by casein kinase II (CKII) significantly upregulated traction forces and total strain energy generated fibroblasts on nanopillar arrays, consequently other elementary functions including spreading metabolic...
Generating and maintaining gradients of cell density extracellular matrix (ECM) components is a prerequisite for the development functionality healthy tissue. Therefore, gaining insights into drivers spatial organization cells role ECM during tissue morphogenesis vital. In 3D model system morphogenesis, fibronectin-FRET sensor recently revealed existence two separate fibronectin populations with different conformations in microtissues, i.e. 'compact adsorbed to collagen' versus 'extended...
Fibronectin is a globular protein that circulates in the blood and undergoes fibrillogenesis if stretched or under other partially denaturing conditions, even absence of cells.Stretch assays made by pulling fibers from droplets solutions containing high concentrations fibronectin have previously been introduced mechanobiology, particularly to ask how bacteria cells exploit stretching within extracellular matrix mechano-regulate its chemical display.Our electron microscopy analysis their...
Angiogenesis and lymphangiogenesis are highly complex morphogenetic processes, central to many physiological pathological conditions, including development, cancer metastasis, inflammation wound healing. While it is described that extracellular matrix (ECM) fibers involved in the spatiotemporal regulation of angiogenesis, current angiogenesis assays not specifically designed dissect quantify underlying molecular mechanisms how fibrillar nature ECM regulates vessel sprouting. Even less known...
Physical interactions between vascular endothelial growth factor (VEGF), a central player in blood cell biology, and fibronectin, major fibrillar protein of the extracellular matrix, are important determinants angiogenic activity health disease. Conditions signaling need for new vessel growth, such as hypoxia low pH, increase VEGF–fibronectin interactions. These can be further fine-tuned through changes availability VEGF-binding sites on regulated by conformational induced heparin heparan...
Growth factors regulate a diverse array of cellular functions including proliferation, survival, movement, and the ability to do this often involves interactions with extracellular matrix (ECM) particularly heparan sulfate proteoglycans (HSPGs). HSPGs have been shown sequester growth factors, act as factor co-receptors or receptors themselves. Recent studies, however, revealed new role for in mediating ECM. Specifically, has modulate fibronectin structure reveal previously masked binding...
Abstract A straightforward strategy is presented for the site‐specific incorporation of fluorophores or reactive probes into extracellular matrix (ECM) protein fibronectin (Fn) by using enzyme‐catalyzed transamidation activated factor XIII. Characterization SDS‐PAGE, western blotting, absorption measurements, mass spectrometry, and stepwise photobleaching labeling quantification at single‐molecule level showed that was efficient restricted to N‐terminal tails. The introduction labels did not...
<p>Table S4: Primers used for site-directed mutagenesis. The mutated nucleotides are indicated in bold and underlined each mutant.</p>
<p>Table S3: Treatment regimens of the Avatar patient derived xenograft models carrying VEGFR2 WT and L840F genotypes.</p>
<p>Figure S5: A) Levels of phosphorylated ERK following treatment the MDST8 colorectal cell line, expressing R1032Q VEGFR2, with different kinase inhibitors in presence. B) Proliferation assays Colo320 lines, stably WT and upon TKIs. The expression VEGFR2 hot-spot mutant lines (WT to KRAS/NRAS/BRAF/PIK3CA mutated TP53 APC) increased sensitivity cabozantinib.</p>
<p>Figure S4: A) Molecular dynamics simulations with L840F VEGFR2 indicates that most of the adopted F840 conformations during simulation are not compatible inhibitor binding. Clashes between and sorafenib area shown as red discs. B) Kinase assays showing impaired kinase activities R1032Q compared to wild-type. C) Effects mutation on Y1175 phosphorylation. HEK293 cells were transiently transfected increasing levels a plasmid encoding for WT or VEGFR2. Cells at 70% confluence starved in...
<p>Legends for Supplementary Figures 1-6</p>
<p>Detailed methods</p>
<p>Figure S6: Assessment of the expression phosphorylated ERK (p-ERK) in WT and L840F VEGFR2 PDX Avatar models by immunohistochemistry (A), confocal microscopy (B), immunoblotting (C). The MAPK pathway was activated mutant model not decreased following treatment with TKIs.</p>