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Dr. Johannes Eble
University of Münster, Institute of Physiological Chemistry and Pathobiochemistry

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0 Extracellular Matrix
0 integrins
0 snake venoms
0 integrin adhesion complex
0 redox-regulation

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Review
Published: 16 April 2021 in Frontiers in Cell and Developmental Biology
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Although platelets and the coagulation factors are components of the blood system, they become part of and contribute to the tumor microenvironment (TME) not only within a solid tumor mass, but also within a hematogenous micrometastasis on its way through the blood stream to the metastatic niche. The latter basically consists of blood-borne cancer cells which are in close association with platelets. At the site of the primary tumor, the blood components reach the TME via leaky blood vessels, whose permeability is increased by tumor-secreted growth factors, by incomplete angiogenic sprouts or by vasculogenic mimicry (VM) vessels. As a consequence, platelets reach the primary tumor via several cell adhesion molecules (CAMs). Moreover, clotting factor VII from the blood associates with tissue factor (TF) that is abundantly expressed on cancer cells. This extrinsic tenase complex turns on the coagulation cascade, which encompasses the activation of thrombin and conversion of soluble fibrinogen into insoluble fibrin. The presence of platelets and their release of growth factors, as well as fibrin deposition changes the TME of a solid tumor mass substantially, thereby promoting tumor progression. Disseminating cancer cells that circulate in the blood stream also recruit platelets, primarily by direct cell-cell interactions via different receptor-counterreceptor pairs and indirectly by fibrin, which bridges the two cell types via different integrin receptors. These tumor cell-platelet aggregates are hematogenous micrometastases, in which platelets and fibrin constitute a particular TME in favor of the cancer cells. Even at the distant site of settlement, the accompanying platelets help the tumor cell to attach and to grow into metastases. Understanding the close liaison of cancer cells with platelets and coagulation factors that change the TME during tumor progression and spreading will help to curb different steps of the metastatic cascade and may help to reduce tumor-induced thrombosis.

ACS Style

Wolfgang M. J. Obermann; Katrin Brockhaus; Johannes A. Eble. Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment. Frontiers in Cell and Developmental Biology 2021, 9, 1 .

AMA Style

Wolfgang M. J. Obermann, Katrin Brockhaus, Johannes A. Eble. Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment. Frontiers in Cell and Developmental Biology. 2021; 9 ():1.

Chicago/Turabian Style

Wolfgang M. J. Obermann; Katrin Brockhaus; Johannes A. Eble. 2021. "Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment." Frontiers in Cell and Developmental Biology 9, no. : 1.

Journal article
Published: 24 March 2021 in International Journal of Molecular Sciences
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Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.

ACS Style

María Barrachina; Irene Izquierdo; Lidia Hermida-Nogueira; Luis Morán; Amparo Pérez; Ana Arroyo; Nuria García-Barberá; Rocío González-Conejero; Sara Troitiño; Johannes Eble; José Rivera; Constantino Martínez; María Loza; Eduardo Domínguez; Ángel García. The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential. International Journal of Molecular Sciences 2021, 22, 3304 .

AMA Style

María Barrachina, Irene Izquierdo, Lidia Hermida-Nogueira, Luis Morán, Amparo Pérez, Ana Arroyo, Nuria García-Barberá, Rocío González-Conejero, Sara Troitiño, Johannes Eble, José Rivera, Constantino Martínez, María Loza, Eduardo Domínguez, Ángel García. The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential. International Journal of Molecular Sciences. 2021; 22 (7):3304.

Chicago/Turabian Style

María Barrachina; Irene Izquierdo; Lidia Hermida-Nogueira; Luis Morán; Amparo Pérez; Ana Arroyo; Nuria García-Barberá; Rocío González-Conejero; Sara Troitiño; Johannes Eble; José Rivera; Constantino Martínez; María Loza; Eduardo Domínguez; Ángel García. 2021. "The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential." International Journal of Molecular Sciences 22, no. 7: 3304.

Journal article
Published: 04 February 2021 in Biochimie
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Glycoprotein (GP)Ib that binds von Willebrand factor (vWF) and glycoprotein (GP)VI, that binds collagen play a significant role in platelet activation and aggregation, and are potential targets for antithrombotic treatment. They are targeted by snake venom proteinases. The effect of a such proteinase, mutalysin-II, on platelet aggregation was examined using washed human platelets and platelet-rich plasma. Its proteolytic activity on vWF, on its binding partner GPIbα, and on GPVI was analyzed by SDS-PAGE, and immunodetection with the corresponding antibodies after blotting. Dose- and time-dependently, mutalysin-II inhibits aggregation of washed platelets induced by vWF plus ristocetin and by convulxin, but with no significant effect on platelet-rich-plasma. Furthermore, mutalysin-II cleaves vWF into low molecular mass multimers of vWF and a rvWF-A1 domain to realease a ∼27-kDa fragment detectable by SDS-PAGE and blotting with mouse anti-rvWF-A1-domain IgG. Moreover, GPVI was cut by mutalysin-II into a soluble ∼55-kDa ectodomain and a fragment of ∼35-kDa. Thus, mutalysin-II inhibits vWF-induced platelet aggregation via cleavage of bound vWF-A1, and its receptor GPIbα. The additional cleavage of, GPVI, blocks collagen-induced platelets. Our data highlight mutalysin-II as an interesting platelet-directed tool targeting vWF-GPIbα binding and particularly GPVI. Thus, it might be suited for antithrombotic therapy as its combined inactivation of two receptors does not significantly compromise hemostasis, but shows high efficacy and safety. Studies are needed to further develop and demonstrate its potential benefits.

ACS Style

Eladio.F. Sanchez; Valeria.G. Alvarenga; Luciana.S. Oliveira; Débora.L. Oliveira; Maria.I. Estevao- Costa; Renzo Flores-Ortiz; Johannes.A. Eble. A fibrinolytic snake venom metalloproteinase, mutalysin-II, with antiplatelet activity and targeting capability toward glycoprotein GPIbα and glycoprotein GPVI. Biochimie 2021, 184, 1 -7.

AMA Style

Eladio.F. Sanchez, Valeria.G. Alvarenga, Luciana.S. Oliveira, Débora.L. Oliveira, Maria.I. Estevao- Costa, Renzo Flores-Ortiz, Johannes.A. Eble. A fibrinolytic snake venom metalloproteinase, mutalysin-II, with antiplatelet activity and targeting capability toward glycoprotein GPIbα and glycoprotein GPVI. Biochimie. 2021; 184 ():1-7.

Chicago/Turabian Style

Eladio.F. Sanchez; Valeria.G. Alvarenga; Luciana.S. Oliveira; Débora.L. Oliveira; Maria.I. Estevao- Costa; Renzo Flores-Ortiz; Johannes.A. Eble. 2021. "A fibrinolytic snake venom metalloproteinase, mutalysin-II, with antiplatelet activity and targeting capability toward glycoprotein GPIbα and glycoprotein GPVI." Biochimie 184, no. : 1-7.

Journal article
Published: 16 January 2021 in Free Radical Biology and Medicine
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Proteomics studies have revealed that adhesomes are assembled from a plethora of proteins at integrin-mediated cellular contact sites with the extracellular matrix. By combining dimedone-trapping of sulfenylated proteins with the purification of the adhesome complex, we extended previous proteomics approaches on adhesomes to a redox proteomic analysis. This added a new aspect of adhesome complexity as individual adhesome proteins change their redox state in response to environmental signals. As model system, rat pheochromocytoma PC12 cells were studied in contact with type IV collagen and in response to nerve growth factor (NGF). NGF stimulates the endogenous production of reactive oxygen species (ROS) and the formation of neurite-like cell protrusions, which are anchored to the substratum via adhesomes. Dimedone detects the reversible oxidation of cysteine thiol groups into sulfenic acid groups which was used in proteomic analysis of adhesome proteins revealing that sulfenylation and location of proteins mutually influence each other. For some proteins, identified by the redox proteomics approach, among them Nck-associated protein-1 (Nap-1), proximity ligation analysis and co-immunoprecipitation assays proved that protein sulfenylation sites colocalize with adhesomes of protrusions. In conclusion, the suprastructural composition and function of adhesomes is redox-regulated by ROS. Of interest in this respect, isoform-selective pharmacological inhibition of NADPH-oxidases (Noxs) reduced the adhesomal location of the collagen-binding α1β1 integrin and the length of the outgrowing neurites, indicative of a role of Nox isoforms in the redox-regulation of adhesomes. Thus, our novel redox proteomics approach not only revealed redox-modifications and the potential redox-regulation of adhesomes and their constituents but it may also provide a tool to analyze the ROS-stimulated neurite repair of peripheral neurons.

ACS Style

Juliane Meißner; Maryam Rezaei; Isabel Siepe; Doreen Ackermann; Simone König; Johannes A. Eble. Redox proteomics reveals an interdependence of redox modification and location of adhesome proteins in NGF-treated PC12 cells. Free Radical Biology and Medicine 2021, 164, 341 -353.

AMA Style

Juliane Meißner, Maryam Rezaei, Isabel Siepe, Doreen Ackermann, Simone König, Johannes A. Eble. Redox proteomics reveals an interdependence of redox modification and location of adhesome proteins in NGF-treated PC12 cells. Free Radical Biology and Medicine. 2021; 164 ():341-353.

Chicago/Turabian Style

Juliane Meißner; Maryam Rezaei; Isabel Siepe; Doreen Ackermann; Simone König; Johannes A. Eble. 2021. "Redox proteomics reveals an interdependence of redox modification and location of adhesome proteins in NGF-treated PC12 cells." Free Radical Biology and Medicine 164, no. : 341-353.

Review
Published: 28 December 2020 in International Journal of Molecular Sciences
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The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME. The cells of the TME modify their surrounding cancer-characteristic ECM. This in turn provides feedback to them via cellular receptors, thereby regulating, together with cytokines and exosomes, differentiation processes as well as tumor progression and spread. Matrix remodeling is accomplished by altering the repertoire of ECM components and by biophysical changes in stiffness and tension caused by ECM-crosslinking and ECM-degrading enzymes, in particular matrix metalloproteinases (MMPs). These can degrade ECM barriers or, by partial proteolysis, release soluble ECM fragments called matrikines, which influence cells inside and outside the TME. This review examines the changes in the ECM of the TME and the interaction between cells and the ECM, with a particular focus on MMPs.

ACS Style

Stephan Niland; Johannes A. Eble. Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment. International Journal of Molecular Sciences 2020, 22, 238 .

AMA Style

Stephan Niland, Johannes A. Eble. Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment. International Journal of Molecular Sciences. 2020; 22 (1):238.

Chicago/Turabian Style

Stephan Niland; Johannes A. Eble. 2020. "Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 1: 238.

Journal article
Published: 28 October 2020 in Biological Chemistry
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Redox-mediated signal transduction depends on the enzymatic production of second messengers such as hydrogen peroxide, nitric oxide and hydrogen sulfite, as well as specific, reversible redox modifications of cysteine-residues in proteins. So-called thiol switches induce for instance conformational changes in specific proteins that regulate cellular pathways e.g., cell metabolism, proliferation, migration, gene expression and inflammation. Reduction, oxidation and disulfide isomerization are controlled by oxidoreductases of the thioredoxin family, including thioredoxins, glutaredoxins, peroxiredoxins and protein dsisulfide isomerases. These proteins are located in different cellular compartments, interact with substrates and catalyze specific reactions. Interestingly, some of these proteins are released by cells. Their extracellular functions and generally extracellular redox control have been widely underestimated. Here, we give an insight into extracellular redox signaling, extracellular thiol switches and their regulation by secreted oxidoreductases and thiol-isomerases, a topic whose importance has been scarcely studied so far, likely due to methodological limitations. We focus on the secreted redox proteins and characterized thiol switches in the ectodomains of membrane proteins, such as integrins and the metalloprotease ADAM17, which are among the best-characterized proteins and discuss their underlying mechanisms and biological implications.

ACS Style

Inken Lorenzen; Johannes A. Eble; Eva-Maria Hanschmann. Thiol switches in membrane proteins - Extracellular redox regulation in cell biology. Biological Chemistry 2020, 402, 253 -269.

AMA Style

Inken Lorenzen, Johannes A. Eble, Eva-Maria Hanschmann. Thiol switches in membrane proteins - Extracellular redox regulation in cell biology. Biological Chemistry. 2020; 402 (3):253-269.

Chicago/Turabian Style

Inken Lorenzen; Johannes A. Eble; Eva-Maria Hanschmann. 2020. "Thiol switches in membrane proteins - Extracellular redox regulation in cell biology." Biological Chemistry 402, no. 3: 253-269.

Journal article
Published: 01 August 2020 in Cancers
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Cadherins mediate cohesive contacts between isotypic cells by homophilic interaction and prevent contact between heterotypic cells. Breast cancer cells neighboring endothelial cells (ECs) atypically express vascular endothelial (VE)-cadherin. To understand this EC-induced VE-cadherin expression in breast cancer cells, MCF7 and MDA-MB-231 cells expressing different endogenous cadherins were co-cultured with ECs and analyzed for VE-cadherin at the transcriptional level and by confocal microscopy, flow cytometry, and immunoblotting. After losing their endogenous cadherins and neo-expression of VE-cadherin, these cells integrated into an EC monolayer without compromising the barrier function instantly. However, they induced the death of nearby ECs. EC-derived extracellular vesicles (EVs) contained soluble and membrane-anchored forms of VE-cadherin. Only the latter was re-utilized by the cancer cells. In a reporter gene assay, EC-adjacent cancer cells also showed a juxtacrine but no paracrine activation of the endogenous VE-cadherin gene. This cadherin switch enabled intimate contact between cancer and endothelial cells in a chicken chorioallantoic membrane tumor model showing vasculogenic mimicry (VM). This EV-mediated, EC-induced cadherin switch in breast cancer cells and the neo-expression of VE-cadherin mechanistically explain the mutual communication in the tumor microenvironment. Hence, it may be a target to tackle VM, which is often found in breast cancers of poor prognosis.

ACS Style

Maryam Rezaei; Ana C. Martins Cavaco; Martin Stehling; Astrid Nottebaum; Katrin Brockhaus; Michele F. Caliandro; Sonja Schelhaas; Felix Schmalbein; Dietmar Vestweber; Johannes A. Eble. Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts. Cancers 2020, 12, 2138 .

AMA Style

Maryam Rezaei, Ana C. Martins Cavaco, Martin Stehling, Astrid Nottebaum, Katrin Brockhaus, Michele F. Caliandro, Sonja Schelhaas, Felix Schmalbein, Dietmar Vestweber, Johannes A. Eble. Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts. Cancers. 2020; 12 (8):2138.

Chicago/Turabian Style

Maryam Rezaei; Ana C. Martins Cavaco; Martin Stehling; Astrid Nottebaum; Katrin Brockhaus; Michele F. Caliandro; Sonja Schelhaas; Felix Schmalbein; Dietmar Vestweber; Johannes A. Eble. 2020. "Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts." Cancers 12, no. 8: 2138.

Journal article
Published: 25 June 2020 in Cancers
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

ACS Style

Isabelle Flammang; Moritz Reese; Zixuan Yang; Johannes A. Eble; Sameer A. Dhayat. Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma. Cancers 2020, 12, 1693 .

AMA Style

Isabelle Flammang, Moritz Reese, Zixuan Yang, Johannes A. Eble, Sameer A. Dhayat. Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma. Cancers. 2020; 12 (6):1693.

Chicago/Turabian Style

Isabelle Flammang; Moritz Reese; Zixuan Yang; Johannes A. Eble; Sameer A. Dhayat. 2020. "Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma." Cancers 12, no. 6: 1693.

Journal article
Published: 10 March 2020 in Antioxidants
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While adhering to extracellular matrix (ECM) proteins, such as laminin-111, cells temporarily produce hydrogen peroxide at adhesion sites. To study the redox regulation of α7β1 integrin-mediated cell adhesion to laminin-111, a conserved cysteine pair within the α-subunit hinge region was replaced for alanines. The molecular and cellular effects were analyzed by electron and atomic force microscopy, impedance-based migration assays, flow cytometry and live cell imaging. This cysteine pair constitutes a thiol-switch, which redox-dependently governs the equilibrium between an extended and a bent integrin conformation with high and low ligand binding activity, respectively. Hydrogen peroxide oxidizes the cysteines to a disulfide bond, increases ligand binding and promotes cell migration toward laminin-111. Inversely, extracellular thioredoxin-1 reduces the disulfide, thereby decreasing laminin binding. Mutation of this cysteine pair into the non-oxidizable hinge-mutant shows molecular and cellular effects similar to the reduced wild-type integrin, but lacks redox regulation. This proves the existence of a dominant thiol-switch within the α subunit hinge of α7β1 integrin, which is sufficient to implement activity regulation by extracellular redox agents in a redox-regulatory circuit. Our data reveal a novel and physiologically relevant thiol-based regulatory mechanism of integrin-mediated cell-ECM interactions, which employs short-lived hydrogen peroxide and extracellular thioredoxin-1 as signaling mediators.

ACS Style

Lukas Bergerhausen; Julius Grosche; Juliane Meißner; Christina Hecker; Michele F. Caliandro; Christoph Westerhausen; Andrej Kamenac; Maryam Rezaei; Matthias Mörgelin; Gereon Poschmann; Dietmar Vestweber; Eva-Maria Hanschmann; Johannes A. Eble. Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch. Antioxidants 2020, 9, 227 .

AMA Style

Lukas Bergerhausen, Julius Grosche, Juliane Meißner, Christina Hecker, Michele F. Caliandro, Christoph Westerhausen, Andrej Kamenac, Maryam Rezaei, Matthias Mörgelin, Gereon Poschmann, Dietmar Vestweber, Eva-Maria Hanschmann, Johannes A. Eble. Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch. Antioxidants. 2020; 9 (3):227.

Chicago/Turabian Style

Lukas Bergerhausen; Julius Grosche; Juliane Meißner; Christina Hecker; Michele F. Caliandro; Christoph Westerhausen; Andrej Kamenac; Maryam Rezaei; Matthias Mörgelin; Gereon Poschmann; Dietmar Vestweber; Eva-Maria Hanschmann; Johannes A. Eble. 2020. "Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch." Antioxidants 9, no. 3: 227.

Chapter
Published: 07 February 2020 in Advances in Experimental Medicine and Biology
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Neuropilin-1 and neuropilin-2 form a small family of transmembrane receptors, which, due to the lack of a cytosolic protein kinase domain, act primarily as co-receptors for various ligands. Performing at the molecular level both the executive and organizing functions of a handyman as well as of a power broker, they are instrumental in controlling the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. In this setting, the various neuropilin ligands and interaction partners on various cells of the tumor microenvironment, such as cancer cells, endothelial cells, cancer-associated fibroblasts, and immune cells, are surveyed. The suitability of various neuropilin-targeting substances and the intervention in neuropilin-mediated interactions is considered as a possible building block of tumor therapy.

ACS Style

Stephan Niland; Johannes A. Eble. Neuropilin: Handyman and Power Broker in the Tumor Microenvironment. Advances in Experimental Medicine and Biology 2020, 1223, 31 -67.

AMA Style

Stephan Niland, Johannes A. Eble. Neuropilin: Handyman and Power Broker in the Tumor Microenvironment. Advances in Experimental Medicine and Biology. 2020; 1223 ():31-67.

Chicago/Turabian Style

Stephan Niland; Johannes A. Eble. 2020. "Neuropilin: Handyman and Power Broker in the Tumor Microenvironment." Advances in Experimental Medicine and Biology 1223, no. : 31-67.

Journal article
Published: 26 September 2019 in Molecules
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Atroxlysin-III (Atr-III) was purified from the venom of Bothrops atrox. This 56-kDa protein bears N-linked glycoconjugates and is a P-III hemorrhagic metalloproteinase. Its cDNA-deduced amino acid sequence reveals a multidomain structure including a proprotein, a metalloproteinase, a disintegrin-like and a cysteine-rich domain. Its identity with bothropasin and jararhagin from Bothrops jararaca is 97% and 95%, respectively. Its enzymatic activity is metal ion-dependent. The divalent cations, Mg2+ and Ca2+, enhance its activity, whereas excess Zn2+ inhibits it. Chemical modification of the Zn2+-complexing histidine residues within the active site by using diethylpyrocarbonate (DEPC) inactivates it. Atr-III degrades plasma fibronectin, type I-collagen, and mainly the α-chains of fibrinogen and fibrin. The von Willebrand factor (vWF) A1-domain, which harbors the binding site for GPIb, is not hydrolyzed. Platelets interact with collagen via receptors for collagen, glycoprotein VI (GPVI), and α2β1 integrin. Neither the α2β1 integrin nor its collagen-binding A-domain is fragmented by Atr-III. In contrast, Atr-III cleaves glycoprotein VI (GPVI) into a soluble ~55-kDa fragment (sGPVI). Thereby, it inhibits aggregation of platelets which had been stimulated by convulxin, a GPVI agonist. Selectively, Atr-III targets GPVI antagonistically and thus contributes to the antithrombotic effect of envenomation by Bothrops atrox.

ACS Style

Luciana S. Oliveira; Maria Inácia Estevão-Costa; Valéria G. Alvarenga; Dan E. Vivas-Ruiz; Armando Yarleque; Augusto Martins Lima; Ana Cavaco; Johannes A. Eble; Eladio F. Sanchez. Atroxlysin-III, A Metalloproteinase from the Venom of the Peruvian Pit Viper Snake Bothrops atrox (Jergón) Induces Glycoprotein VI Shedding and Impairs Platelet Function. Molecules 2019, 24, 3489 .

AMA Style

Luciana S. Oliveira, Maria Inácia Estevão-Costa, Valéria G. Alvarenga, Dan E. Vivas-Ruiz, Armando Yarleque, Augusto Martins Lima, Ana Cavaco, Johannes A. Eble, Eladio F. Sanchez. Atroxlysin-III, A Metalloproteinase from the Venom of the Peruvian Pit Viper Snake Bothrops atrox (Jergón) Induces Glycoprotein VI Shedding and Impairs Platelet Function. Molecules. 2019; 24 (19):3489.

Chicago/Turabian Style

Luciana S. Oliveira; Maria Inácia Estevão-Costa; Valéria G. Alvarenga; Dan E. Vivas-Ruiz; Armando Yarleque; Augusto Martins Lima; Ana Cavaco; Johannes A. Eble; Eladio F. Sanchez. 2019. "Atroxlysin-III, A Metalloproteinase from the Venom of the Peruvian Pit Viper Snake Bothrops atrox (Jergón) Induces Glycoprotein VI Shedding and Impairs Platelet Function." Molecules 24, no. 19: 3489.

Editorial
Published: 03 September 2019 in Cancers
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In recent years the tumor microenvironment (TME) has received increasing attention [...].

ACS Style

Johannes A. Eble; Donald Gullberg. What Is the Fuss about Integrins and the Tumor Microenvironment? Cancers 2019, 11, 1296 .

AMA Style

Johannes A. Eble, Donald Gullberg. What Is the Fuss about Integrins and the Tumor Microenvironment? Cancers. 2019; 11 (9):1296.

Chicago/Turabian Style

Johannes A. Eble; Donald Gullberg. 2019. "What Is the Fuss about Integrins and the Tumor Microenvironment?" Cancers 11, no. 9: 1296.

Video audio media
Published: 08 August 2019 in Journal of Visualized Experiments
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Defining the ideal model for an in vitro study is essential, mainly if studying physiological processes such as differentiation of cells. In the tumor stroma, host fibroblasts are stimulated by cancer cells to differentiate. Thus, they acquire a phenotype that contributes to the tumor microenvironment and supports tumor progression. By using the spheroid model, we have set up such a 3D in vitro model system, in which we analyzed the role of laminin-332 and its receptor integrin α3β1 in this differentiation process. This spheroid model system not only reproduces the tumor microenvironment conditions in a more accurate way, but also is a very versatile model since it allows different downstream studies, such as immunofluorescent staining of both intra- and extracellular markers, as well as deposited extracellular matrix proteins. Moreover, transcriptional analyses by qPCR, flow cytometry and cellular invasion can be studied with this model. Here, we describe a protocol of a spheroid model to assess the role of CAFs' integrin α3β1 and its ectopically deposited ligand, laminin-332, in differentiation and in supporting the invasion of pancreatic cancer cells.

ACS Style

Ana C. Martins Cavaco; Johannes A. Eble. A 3D Spheroid Model as a More Physiological System for Cancer-Associated Fibroblasts Differentiation and Invasion In Vitro Studies. Journal of Visualized Experiments 2019, 1 .

AMA Style

Ana C. Martins Cavaco, Johannes A. Eble. A 3D Spheroid Model as a More Physiological System for Cancer-Associated Fibroblasts Differentiation and Invasion In Vitro Studies. Journal of Visualized Experiments. 2019; (150):1.

Chicago/Turabian Style

Ana C. Martins Cavaco; Johannes A. Eble. 2019. "A 3D Spheroid Model as a More Physiological System for Cancer-Associated Fibroblasts Differentiation and Invasion In Vitro Studies." Journal of Visualized Experiments , no. 150: 1.

Review
Published: 11 April 2019 in Clinical & Experimental Metastasis
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The extracellular matrix (ECM) constitutes the scaffold of tissues and organs. It is a complex network of extracellular proteins, proteoglycans and glycoproteins, which form supramolecular aggregates, such as fibrils and sheet-like networks. In addition to its biochemical composition, including the covalent intermolecular cross-linkages, the ECM is also characterized by its biophysical parameters, such as topography, molecular density, stiffness/rigidity and tension. Taking these biochemical and biophysical parameters into consideration, the ECM is very versatile and undergoes constant remodeling. This review focusses on this remodeling of the ECM under the influence of a primary solid tumor mass. Within this tumor stroma, not only the cancer cells but also the resident fibroblasts, which differentiate into cancer-associated fibroblasts (CAFs), modify the ECM. Growth factors and chemokines, which are tethered to and released from the ECM, as well as metabolic changes of the cells within the tumor bulk, add to the tumor-supporting tumor microenvironment. Metastasizing cancer cells from a primary tumor mass infiltrate into the ECM, which variably may facilitate cancer cell migration or act as barrier, which has to be proteolytically breached by the infiltrating tumor cell. The biochemical and biophysical properties therefore determine the rates and routes of metastatic dissemination. Moreover, primed by soluble factors of the primary tumor, the ECM of distant organs may be remodeled in a way to facilitate the engraftment of metastasizing cancer cells. Such premetastatic niches are responsible for the organotropic preference of certain cancer entities to colonize at certain sites in distant organs and to establish a metastasis. Translational application of our knowledge about the cancer-primed ECM is sparse with respect to therapeutic approaches, whereas tumor-induced ECM alterations such as increased tissue stiffness and desmoplasia, as well as breaching the basement membrane are hallmark of malignancy and diagnostically and histologically harnessed.

ACS Style

Johannes A. Eble; Stephan Niland. The extracellular matrix in tumor progression and metastasis. Clinical & Experimental Metastasis 2019, 36, 171 -198.

AMA Style

Johannes A. Eble, Stephan Niland. The extracellular matrix in tumor progression and metastasis. Clinical & Experimental Metastasis. 2019; 36 (3):171-198.

Chicago/Turabian Style

Johannes A. Eble; Stephan Niland. 2019. "The extracellular matrix in tumor progression and metastasis." Clinical & Experimental Metastasis 36, no. 3: 171-198.

Review
Published: 01 March 2019 in Toxins
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Snake venoms contain an astounding variety of different proteins. Among them are numerous C-type lectin family members, which are grouped into classical Ca2+- and sugar-binding lectins and the non-sugar-binding snake venom C-type lectin-related proteins (SV-CLRPs), also called snaclecs. Both groups share the robust C-type lectin domain (CTLD) fold but differ in a long loop, which either contributes to a sugar-binding site or is expanded into a loop-swapping heterodimerization domain between two CLRP subunits. Most C-type lectin (-related) proteins assemble in ordered supramolecular complexes with a high versatility of subunit numbers and geometric arrays. Similarly versatile is their ability to inhibit or block their target molecules as well as to agonistically stimulate or antagonistically blunt a cellular reaction triggered by their target receptor. By utilizing distinct interaction sites differentially, SV-CLRPs target a plethora of molecules, such as distinct coagulation factors and receptors of platelets and endothelial cells that are involved in hemostasis, thrombus formation, inflammation and hematogenous metastasis. Because of their robust structure and their high affinity towards their clinically relevant targets, SV-CLRPs are and will potentially be valuable prototypes to develop new diagnostic and therapeutic tools in medicine, provided that the molecular mechanisms underlying their versatility are disclosed.

ACS Style

Johannes A. Eble. Structurally Robust and Functionally Highly Versatile—C-Type Lectin (-Related) Proteins in Snake Venoms. Toxins 2019, 11, 136 .

AMA Style

Johannes A. Eble. Structurally Robust and Functionally Highly Versatile—C-Type Lectin (-Related) Proteins in Snake Venoms. Toxins. 2019; 11 (3):136.

Chicago/Turabian Style

Johannes A. Eble. 2019. "Structurally Robust and Functionally Highly Versatile—C-Type Lectin (-Related) Proteins in Snake Venoms." Toxins 11, no. 3: 136.

Review
Published: 01 February 2019 in International Journal of Molecular Sciences
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Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed.

ACS Style

Stephan Niland; Johannes A. Eble. Neuropilins in the Context of Tumor Vasculature. International Journal of Molecular Sciences 2019, 20, 639 .

AMA Style

Stephan Niland, Johannes A. Eble. Neuropilins in the Context of Tumor Vasculature. International Journal of Molecular Sciences. 2019; 20 (3):639.

Chicago/Turabian Style

Stephan Niland; Johannes A. Eble. 2019. "Neuropilins in the Context of Tumor Vasculature." International Journal of Molecular Sciences 20, no. 3: 639.

Journal article
Published: 28 January 2019 in The Journal of Immunology
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The neuropilin-1 (NRP1)-MET signaling axis regulates the motility of individual endothelial cells (ECs). It is unknown how this signaling pathway affects the endothelial barrier in coherent ECs forming a tight monolayer. We hypothesized that it is involved both in modulation of the endothelial barrier and in EC activation. To investigate the role of NRP1–MET signaling in inflammatory processes (e.g., systemic inflammatory response syndrome [SIRS] or snakebite-induced SIRS-like conditions), we employed the C-type lectin-related protein rhodocetin-αβ (RCαβ) as a specific trigger of this signal axis in ECs in vitro. In coherent HUVECs, RCαβ reinforced the actin cytoskeleton and increased cell stiffness, thus favoring vascular endothelial cadherin–mediated transmission of intercellular forces. Increased cell stiffness was associated with enhanced activation of RhoA and nuclear translocation of NF-κB. Simultaneously, RCαβ-triggered signaling via the NRP1–MET axis increased EC monolayer permeability, induced transcription of proinflammatory genes such as ICAM-1 and, consequently, leukocyte tethering. The RCαβ-induced transcriptome differed from that induced by hepatocyte growth factor, although in both cases the same tyrosine kinase, MET, was involved. This was due to RCαβ-mediated recruitment of the MET coreceptor NRP1 and additional Rho-mediated activation of the actomyosin system. RCαβ induced similar transcriptional and cellular changes if external shear forces were applied. These data highlight the modulatory role of NRP1 as MET coreceptor, and they explain how some snake venoms induce SIRS-like conditions. Additionally, this study demonstrates that inflammatory activation of coherent ECs is triggered by converging signals that are induced by NRP1–MET signaling and influenced by intercellular forces.

ACS Style

Maryam Rezaei; Ana C. Martins Cavaco; Jochen Seebach; Stephan Niland; Jana Zimmermann; Eva-Maria Hanschmann; Rupert Hallmann; Hermann Schillers; Johannes A. Eble. Signals of the Neuropilin-1–MET Axis and Cues of Mechanical Force Exertion Converge to Elicit Inflammatory Activation in Coherent Endothelial Cells. The Journal of Immunology 2019, 202, 1559 -1572.

AMA Style

Maryam Rezaei, Ana C. Martins Cavaco, Jochen Seebach, Stephan Niland, Jana Zimmermann, Eva-Maria Hanschmann, Rupert Hallmann, Hermann Schillers, Johannes A. Eble. Signals of the Neuropilin-1–MET Axis and Cues of Mechanical Force Exertion Converge to Elicit Inflammatory Activation in Coherent Endothelial Cells. The Journal of Immunology. 2019; 202 (5):1559-1572.

Chicago/Turabian Style

Maryam Rezaei; Ana C. Martins Cavaco; Jochen Seebach; Stephan Niland; Jana Zimmermann; Eva-Maria Hanschmann; Rupert Hallmann; Hermann Schillers; Johannes A. Eble. 2019. "Signals of the Neuropilin-1–MET Axis and Cues of Mechanical Force Exertion Converge to Elicit Inflammatory Activation in Coherent Endothelial Cells." The Journal of Immunology 202, no. 5: 1559-1572.

Journal article
Published: 21 December 2018 in Cancers
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Ranking among the most lethal tumour entities, pancreatic duct adenocarcinoma cells invade neighbouring tissue resulting in high incidence of metastasis. They are supported by tumour stroma fibroblasts which have undergone differentiation into cancer-associated fibroblasts (CAFs). Stiffness of cell substratum, cytokines, such as transforming growth factor-β (TGF-β), and stromal matrix proteins, such as laminin-332, are factors which promote CAF differentiation. In a spheroid culture system, differentiation of CAFs was analysed for laminin-332 production, laminin-binding integrin repertoire, adhesion and migration behaviour, and, in heterospheroids, for their interplay with the pancreatic duct adenocarcinoma AsPC-I cells. Our data reveal that CAFs produce laminin-332 thus contributing to its ectopic deposition within the tumour stroma. Moreover, CAF differentiation correlates with an increased expression of α3β1 integrin, the principal laminin-332-receptor. Beyond its role as novel CAF marker protein, integrin α3β1 crucially determines differentiation and maintenance of the CAF phenotype, as knock-out of the integrin α3 subunit reversed the CAF differentiated state. AsPC-I cells co-cultured in heterospheroids with integrin α3-deficient CAFs invaded less than from heterospheroids with wild-type CAFs. This study highlights the role of integrin α3β1 integrin-laminin-332 interaction of CAFs which promotes and sustains differentiation of CAFs and promotes carcinoma invasion.

ACS Style

Ana C. Martins Cavaco; Maryam Rezaei; Michele F. Caliandro; Augusto Martins Lima; Martin Stehling; Sameer A. Dhayat; Jörg Haier; Cord Brakebusch; Johannes A. Eble. The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells. Cancers 2018, 11, 14 .

AMA Style

Ana C. Martins Cavaco, Maryam Rezaei, Michele F. Caliandro, Augusto Martins Lima, Martin Stehling, Sameer A. Dhayat, Jörg Haier, Cord Brakebusch, Johannes A. Eble. The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells. Cancers. 2018; 11 (1):14.

Chicago/Turabian Style

Ana C. Martins Cavaco; Maryam Rezaei; Michele F. Caliandro; Augusto Martins Lima; Martin Stehling; Sameer A. Dhayat; Jörg Haier; Cord Brakebusch; Johannes A. Eble. 2018. "The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells." Cancers 11, no. 1: 14.

Review
Published: 01 October 2018 in Molecular Aspects of Medicine
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Fibrosis is characterized by excess deposition of extracellular matrix (ECM). However, the ECM changes during fibrosis not only quantitatively but also qualitatively. Thus, the composition is altered as the expression of various ECM proteins changes. Moreover, also posttranslational modifications, secretion, deposition and crosslinkage as well as the proteolytic degradation of ECM components run differently during fibrosis. As several of these processes involve redox reactions and some of them are even redox-regulated, reactive oxygen species (ROS) influence fibrotic diseases. Redox regulation of the ECM has not been studied intensively, although evidences exist that the alteration of the ECM, including the redox-relevant processes of its formation and degradation, may be of key importance not only as a cause but also as a consequence of fibrotic diseases. Myofibroblasts, which have differentiated from fibroblasts during fibrosis, produce most of the ECM components and in return obtain important environmental cues of the ECM, including their redox-dependent fibrotic alterations. Thus, myofibroblast differentiation and fibrotic changes of the ECM are interdependent processes and linked with each other via cell-matrix contacts, which are mediated by integrins and other cell adhesion molecules. These cell-matrix contacts are also regulated by redox processes and by ROS. However, most of the redox-catalyzing enzymes are localized within cells. Little is known about redox-regulating enzymes, especially the ones that control the formation and cleavage of redox-sensitive disulfide bridges within the extracellular space. They are also important players in the redox-regulative crosstalk between ECM and cells during fibrosis.

ACS Style

Julius Grosche; Juliane Meißner; Johannes A. Eble. More than a syllable in fib-ROS-is: The role of ROS on the fibrotic extracellular matrix and on cellular contacts. Molecular Aspects of Medicine 2018, 63, 30 -46.

AMA Style

Julius Grosche, Juliane Meißner, Johannes A. Eble. More than a syllable in fib-ROS-is: The role of ROS on the fibrotic extracellular matrix and on cellular contacts. Molecular Aspects of Medicine. 2018; 63 ():30-46.

Chicago/Turabian Style

Julius Grosche; Juliane Meißner; Johannes A. Eble. 2018. "More than a syllable in fib-ROS-is: The role of ROS on the fibrotic extracellular matrix and on cellular contacts." Molecular Aspects of Medicine 63, no. : 30-46.

Review article
Published: 24 September 2018 in The International Journal of Biochemistry & Cell Biology
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Both mythologically and logically, snakes have always fascinated man. Snakes have attracted both awe and fear not only because of the elegant movement of their limbless bodies, but also because of the potency of their deadly venoms. Practically, in 2017, the world health organization (WHO) listed snake envenomation as a high priority neglected disease, as snakes inflict up to 2.7 million poisonous bites, around 100.000 casualties, and about three times as many invalidities on man. The venoms of poisonous snakes are a cocktail of potent compounds which specifically and avidly target numerous essential molecules with high efficacy. The individual effects of all venom toxins integrate into lethal dysfunctions of almost any organ system. It is this efficacy and specificity of each venom component, which after analysis of its structure and activity may serve as a potential lead structure for chemical imitation. Such toxin mimetics may help in influencing a specific body function pharmaceutically for the sake of man’s health. In this review article, we will give some examples of snake venom components which have spurred the development of novel pharmaceutical compounds. Moreover, we will provide examples where such snake toxin-derived mimetics are in clinical use, trials, or consideration for further pharmaceutical exploitation, especially in the fields of hemostasis, thrombosis, coagulation, and metastasis. Thus, it becomes clear why a snake captured its symbolic place at the Asclepius rod with good reason still nowadays.

ACS Style

Maria-Inacia Estevão-Costa; Raquel Sanz-Soler; Benjamin Johanningmeier; Johannes A. Eble. Snake venom components in medicine: From the symbolic rod of Asclepius to tangible medical research and application. The International Journal of Biochemistry & Cell Biology 2018, 104, 94 -113.

AMA Style

Maria-Inacia Estevão-Costa, Raquel Sanz-Soler, Benjamin Johanningmeier, Johannes A. Eble. Snake venom components in medicine: From the symbolic rod of Asclepius to tangible medical research and application. The International Journal of Biochemistry & Cell Biology. 2018; 104 ():94-113.

Chicago/Turabian Style

Maria-Inacia Estevão-Costa; Raquel Sanz-Soler; Benjamin Johanningmeier; Johannes A. Eble. 2018. "Snake venom components in medicine: From the symbolic rod of Asclepius to tangible medical research and application." The International Journal of Biochemistry & Cell Biology 104, no. : 94-113.