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Acronym: Angio-Fib - How pericellular matrix orchestrates the angiogenic-to-fibrotic transition

English title Acronym: Angio-Fib - How pericellular matrix orchestrates the angiogenic-to-fibrotic transition
Applicant Vogel Viola
Number 170112
Funding scheme Project funding (Div. I-III)
Research institution Angewandte Mechanobiologie Gesundheitswissenschaften und Technologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Cellular Biology, Cytology
Start/End 01.11.2016 - 31.10.2019
Approved amount 379'120.00
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Keywords (8)

fibronectin; endothelial-to-mesenchymal transition; extracellular matrix; integrins; angiogenesis; fibrosis; tenascin; connective tissue

Lay Summary (German)

Lead
Wie Perizelluläre Matrix den Angiogenese-Fibrose Übergang steuert
Lay summary

Viele unheilbare Krankheiten sind mit der fortschreitenden Umwandlung von vaskularisiertem Gewebe in einen fibrotischen Zustand verbunden. Dieser irreversible Übergang wird begleitet von strukturellen und funktionellen Veränderungen in der Mikrovaskulatur und der Lockerung endothelialer Zell-Zell-Kontakte, die zum Zelltod führen oder den Beginn von Kompensationsmechanismen auslösen können.

Während Vieles über die Akkumulation von extrazellulären Matrix (ECM) -Komponenten während des Beginns der Gewebsfibrose gelernt wurde, ist wenig darüber bekannt, welche molekularen Prozesse zu dieser Transformation führen. Unser übergeordnetes Ziel ist es in Zellkulturen zu verstehen, wie das ECM das Gleichgewicht zwischen Angiogenese und Fibrose reguliert und wie die ECM-Zusammensetzung dieses Gleichgewicht verändern kann.

Direct link to Lay Summary Last update: 08.05.2017

Lay Summary (French)

Lead
Comment la transition angiogenèse - fibrose est régulée par la matrice péri-cellulaire
Lay summary

Beaucoup de maladies graves sont liées à la progression(évolution) d'un tissu sain et bien vascularisé à un tissu fibrotique. Cette transition irréversible est associée à des changements structurels et fonctionnels de la micro-vascularisation et à une réduction de la liaison entre les cellules endothéliales, qui peut amener à la mort cellulaire ou induire des mécanismes compensatoires pathologiques.

Bien que l'accumulation de la matrice extracellulaire pendant la fibrose est relativement bien documentée, les mécanismes responsables de l'initiation de ce changement fibrotique ne sont pas bien connus. Notre but est donc de comprendre, via des expériences en culture cellulaire, comment la matrice extracellulaire est capable de contrôler l'équilibre entre l'angiogenèse et la fibrose, et ainsi de savoir comment la composition de la matrice extracellulaire agit sur cet équilibre.

Direct link to Lay Summary Last update: 08.05.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Nanometric axial resolution of fibronectin assembly units achieved with an efficient reconstruction approach for multi-angle-TIRF microscopy
Soubies Emmanuel, Radwanska Agata, Grall Dominique, Blanc-Féraud Laure, Van Obberghen-Schilling Ellen, Schaub Sébastien (2019), Nanometric axial resolution of fibronectin assembly units achieved with an efficient reconstruction approach for multi-angle-TIRF microscopy, in Scientific Reports, 9(1), 1926-1926.
Counterbalancing anti-adhesive effects of Tenascin-C through fibronectin expression in endothelial cells
Radwanska Agata, Grall Dominique, Schaub Sébastien, Divonne Stéphanie Beghelli-de la Forest, Ciais Delphine, Rekima Samah, Rupp Tristan, Sudaka Anne, Orend Gertraud, Van Obberghen-Schilling Ellen (2017), Counterbalancing anti-adhesive effects of Tenascin-C through fibronectin expression in endothelial cells, in Scientific Reports, 7(1), 12762-12762.

Collaboration

Group / person Country
Types of collaboration
Prof. Martin Bastmeyer, KIT-IFG Karlsruhe; Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Fabiènne Anjuère, Université de Nice France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jozsef Kiss, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Renate Kain, University Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Pr Paul Hofman, CHU Nice France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christel Herold-Mende, University Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Kim Midwood, University Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Joël Guigay, Centre A. Lacassagne France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Alessandra Sacco, The Burnham Institute, La Jolla United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Miguel del Pozo, CNIC, Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Martin Behe, PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Zdenko HERCEG, IARC, Lyon France (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EACR conference: “Goodbye Flat Biology: Advancing 3D-based Models for Cancer Biology and Drug Discovery” Poster Harnessing the potential of a bacterial-derived adhesin and a 3D microtissue platform to bring new insights on ECM fibers tension in tumor 10.11.2019 Berlin, Germany Fonta Charlotte Marie Catherine;
European Association of Cancer Research Conference Series, “Goodbye Flat Biology: Advancing 3D-based Models for Cancer Biology and Drug Discovery” Talk given at a conference Shaping tumors and their microenvironment 10.11.2019 Berlin, Germany Van Obberghen-Schilling Ellen;
Naturwissenschaftliche Gesellschaft Talk given at a conference Mechanobiologie – Neuer Antrieb für vielfältige Innovationen in der Medizin 20.10.2019 Winterthur, Switzerland Vogel Viola;
Seminar at University Moscow Individual talk Roles of tenascin-C in cancer 02.10.2019 Moscow, Russia Orend Gertraud;
GRETSI 2019: 27th Symposium of the Signal and Image Processing Study Group Talk given at a conference Optimal Transport vs Many-to-many assignment for Graph Matching, by Anca-Ioana Grapa 26.08.2019 Lille, France Van Obberghen-Schilling Ellen;
Biointerfaces Intern. Conference Talk given at a conference Keynote: Unraveling the crosstalk between tissue tension and tissue functions 16.08.2019 Zurich, Switzerland Vogel Viola;
Faseb meeting on Matricellular Proteins in Development, Health and Disease Talk given at a conference Roles of tenascin-C in cancer 14.07.2019 Lisbon, Portugal Orend Gertraud;
Imaging in Cancer: Multimodal Analyses Talk given at a conference Digitalized histo-pathology for cancer biology: Deciphering immune-stroma interactions in the tumor microenvironment 27.06.2019 Nice, France Van Obberghen-Schilling Ellen;
Seminar at University Erlangen Individual talk Roles of tenascin-C in cancer 14.06.2019 Erlangen, Germany Orend Gertraud;
LBG Meeting for Health Sciences 2019 Talk given at a conference Mechanobiology: a forceful player in health and disease 11.06.2019 Vienna, Austria Vogel Viola;
Nature conference on Engineering Biology for Medicine Talk given at a conference Nanosensors Engineered for Mechanobiology Applications 20.05.2019 Durham, United States of America Vogel Viola;
XXVIth meeting of the French Society of Extracellular Matrix (SFBMEc) Talk given at a conference Roles of tenascin-C in chronic kidney disease by C. Abou-Faycal 15.05.2019 Reims, France Orend Gertraud;
GRC Conference, Fibronectin, Integrins and Related Molecules Talk given at a conference Mechanobiology of extracellular matrix in healthy and diseased tissues 09.05.2019 Barga Lucca, Italy Vogel Viola;
Gorden Research Conference on Fibronection, Integrins & Related Molecules Talk given at a conference Tumor ECM Microenvironment meets Tumor Immune Microenvironment 05.05.2019 Barga Lucca, Italy Van Obberghen-Schilling Ellen; Bachmann Michael; Orend Gertraud; Wehrle-Haller Bernhard;
Kongress der Deutschen Gesellschaft für Biomechanik Talk given at a conference Keynote: Mechanobiology: a forceful player in health and disease 04.04.2019 Berlin, Germany Vogel Viola;
3rd World Congress on Cancer Biology and Immunology Talk given at a conference Roles of tenascin-C in cancer 01.03.2019 Milano, Italy Orend Gertraud;
15th Winter Brain & Heart Symposium 2019 Talk given at a conference Keynote: Mechanobiology: a forceful player in health and disease 26.02.2019 Sils-Maria, Switzerland Vogel Viola;
GRC Physical Science of Cancer Talk given at a conference Imaging the tensional state of fibronectin fiber tension in tumor stroma 12.02.2019 Galveston, United States of America Vogel Viola;
Orthopaedic Research Society, Annual Meeting Talk given at a conference Spotlight Talk: Mechanobiology: A Rapidly Growing Field with Forceful Implications 04.02.2019 Austin, United States of America Vogel Viola;
Seminar at University Turku Individual talk Roles of tenascin-C in cancer 31.01.2019 Turku, Finland Orend Gertraud;
14th Charles Rodolphe Brupbacher Symposium: “Breakthroughts in Cancer Research and Theraphy” Poster Harnessing a bacterial-derived adhesin as novel probe to read out extracellular matrix fiber tension in tumor tissues 30.01.2019 Zurich, Switzerland Fonta Charlotte Marie Catherine;
European Association of Cancer Research Conference Series, “Goodbye Flat Biology Conference Series, “In Vivo Inspired Cancer Biology and Therapy” Talk given at a conference The ECM Landscape and Tumor Progression” 09.12.2018 Berlin, Germany Van Obberghen-Schilling Ellen;
Basel Breast Consortium (BBC) meeting Talk given at a conference Roles of tenascin-C in cancer 01.12.2018 Basel, Switzerland Orend Gertraud;
Seminar at University Köln Individual talk Roles of tenascin-C in cancer 22.11.2018 Köln, Germany Orend Gertraud;
Chem2Nature Final Conference Talk given at a conference Keynote: How nanoscale insights into bacterial adhesins can drive medical innovations 25.10.2018 Guimares, Portugal Vogel Viola;
RegMed Forum 2018 Talk given at a conference Keynote: Inspired by bacteria: clever nanosensors to measure tissue fiber tension 18.10.2018 Berlin, Germany Vogel Viola;
5th Geneva Diabetes Center Symposium on Metabolism Talk given at a conference The ECM Landscape in health and disease 01.10.2018 Geneva, Switzerland Wehrle-Haller Bernhard; Bachmann Michael; Van Obberghen-Schilling Ellen;
9th Symposium "Physics of Cancer" Talk given at a conference Distinguished: New peptide probes to map the tensional states of ECM fibers in tumour tissues 25.09.2018 Leipzig, Germany Vogel Viola;
29th European Conference on Biomaterials Talk given at a conference Plenary : Mechanobiology: a rapidly growing field with forceful implications 11.09.2018 Maastricht, Netherlands Vogel Viola;
European Association of Cancer Research Conference Series, “Goodbye Flat Biology Conference Series, “In Vivo Inspired Cancer Biology and Therapy” Poster “Fibronectin Splice Variants – Linking the Dots: from mAtrix to metabolism” by Georgious Efthymiou, PhD Student 09.09.2018 Berlin, Germany Van Obberghen-Schilling Ellen;
CLINAM 2018 Talk given at a conference Bacterial Nanoglues Targeting Wound Sites for Theranostic Applications to Read out Tissue Fiber Tensions in Health and Disease 03.09.2018 Basel, Switzerland Vogel Viola;
8th World Congress in Biomechanics Talk given at a conference Keynote: Microtissue Platforms as Cardiovascular Disease Models 12.08.2018 Dublin, Ireland Vogel Viola;
Matrix Biology Europe Talk given at a conference Keynote: Unraveling the Mechanobiology of Extracellular Matrix 23.07.2018 Manchester, Great Britain and Northern Ireland Vogel Viola;
Forces in Cancer: interdisciplinary approaches in tumour Mechanobiology Poster A bacterial fibronectin-binding peptide as a new tool to probe ECM strain state in tumour stroma 18.06.2018 London, Great Britain and Northern Ireland Fonta Charlotte Marie Catherine;
First biomedical symposium at the Lebanese University Talk given at a conference Roles of tenascin-C in chronic kidney disease by C. Abou-Faycal 07.06.2018 Beirut, Lebanon Van Obberghen-Schilling Ellen;
25th Annual meeting of the EUCC (European Cancer Center) Talk given at a conference Roles of tenascin-C in cancer 01.05.2018 Freiburg, Germany Orend Gertraud;
IEEE International Symposium on Biomedical Imaging Poster Classification of fibronectin variants with curvelets by Anca-Ioana Grapa, PhD Student 04.04.2018 Washington, United States of America Van Obberghen-Schilling Ellen;
DPG-Frühjahrstagung 2018 & Condensed Matter Divison der EPS Talk given at a conference Plenary Talk „From Atomistic Simulations into the Mouse: learning how to exploit bacterial adhesives as nanoscale probes to map the mechanical strain of tissue fibers“ 15.03.2018 Berlin, Germany Vogel Viola;
Annual meeting of the German Society for Matrix Biology, DGMB Talk given at a conference Roles of tenascin-C in cancer 01.03.2018 Stuttgart, Germany Orend Gertraud;
Seminar at University Bordeaux Individual talk Roles of tenascin-C in cancer 02.02.2018 Bordeaux, France Orend Gertraud;
French Cancer Society meeting on Mechanics in Cancer Biology Talk given at a conference Reprogramming of the Stromal Matrix 01.12.2017 Paris, France Van Obberghen-Schilling Ellen;
4. Intern. Symposium of the Collaborative Research Center SFB 765, “Mulivalent interactions of Pathogens with Biological Surfaces Talk given at a conference Biomechanics of Bacterial Adhesion 05.10.2017 Berlin, Germany Vogel Viola;
Annual Meeting of the French Society for ECM Biology, Talk given at a conference Plenary lecture: Mechanobiology of extracellular matrix fibers 17.03.2017 Marseille, France Vogel Viola;
Annual Meeting of the French Society for ECM Biology: ECM in Health and Disease Poster Oncofetal fibronectin splice variants : functional analysis and generation of tunable fibroblast-derived extracellular matrices by Agata Radwanska, PhD Student 16.03.2017 Marseille, France Van Obberghen-Schilling Ellen;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Akoya - Phenotypics Applications Meeting Talk 22.05.2019 Uppsala, Sweden Van Obberghen-Schilling Ellen;
Indica Labs’ Paris Quantitative Pathology & HALO User Group Meeting Talk 21.05.2019 Paris, France Van Obberghen-Schilling Ellen;


Awards

Title Year
Chair, 3IA Côte d’Azur (Institut Interdisciplinaire d’Intelligence Artificelle, Côte d’Azur) “AI-powered analysis of the tumor microenvironment” 2019
grant/award from “La Fondation Gertrude von Meissner” based in Geneva. For the project:” Regulation of endothelial function by metabolic imbalance in Type 1 diabetic patients” 2019
Poster-Prize by PhD-Student Georgious Efthymiou: Title: "Fibronectin Splice Variants – Linking the Dots: from mAtrix to metabolism” European Association of Cancer Research Conference Series, “Goodbye Flat Biology Conference Series, “In Vivo Inspired Cancer Biology and Therapy” 2018

Associated projects

Number Title Start Funding scheme
156931 Mechanotransduction processes, from the cell periphery to the nucleus, in 2D versus 3D microenvironments 01.10.2014 Interdisciplinary projects
185261 Regulation of integrin-dependent adhesion-signaling by growth factors and metabolic intermediates 01.04.2019 Project funding (Div. I-III)
175839 Mechanobiology of Extracellular Matrix 01.10.2017 Project funding (Div. I-III)

Abstract

Many incurable diseases are associated with the progressive transformation of vascularized tissue to a fibrotic state. This is accompanied by structural and functional alterations in the microvasculature and the loosening of endothelial cell-cell junctions, which can lead to cell death or trigger the onset of coping mechanisms. While much has been learned about the accumulation of extracellular matrix (ECM) components during the onset of tissue fibrosis, little is known about how the pericellular ECM regulates molecular and cellular signaling events that lead to this transformation. Whereas a variety of receptors can mediate cell binding to the ECM, members of the integrin family at the intersection of ECM and the cytoskeleton are the most well-known and versatile. Our overarching goal is to understand how the ECM regulates the balance between angiogenesis and fibrosis and how its composition and mechanical state can tip this balance to avoid a transition into a fibrotic state. We thus propose to investigate how the composition and mechanobiology of ECM surrounding cells tunes the behavior of endothelial cells, pericytes and fibroblasts leading under certain conditions to an Endothelial-to-Mesenchymal Transition (EndoMT). Antagonistic effects are crucial to the robustness and fine-tuning of biological responses to environmental challenges. Our focus is on elucidating how a few selected molecular ECM players known to counterbalance each other’s effects, synchronize and orchestrate the onset of vascular remodeling and EndoMT. Mostly through our previous research, several key molecules were identified that might play such antagonistic roles, i.e. plasma and cellular fibronectin (FN) versus tenascin-C (TNC), integrin a5ß1 versus a9ß1, and regular versus phosphorylated ECM. This will be clarified by the following aims: Aim 1: Examine the biomechanical properties of FN fibers and how they are altered by the presence of TNC. We will elucidate the counteracting roles of FN and TNC on cell traction forces and ECM remodeling, and determine how this balance is modulated in the presence of ECM made either only from plasma FN (pFN), or made from cellular FN (cFN) that contains the alternative spliced (EDA and EDB) domains. Finally, we will explore how ECM phosphorylation affects the angiogenic versus fibrotic balance since extracellular phosphorylation is primarily associated with pathological states of the ECM, yet very little is known so far how this affects cellular functions. Aim 2: Elucidate the roles of conventional (a5ß1) versus non-conventional (a9ß1) integrins in FN and TNC associated signaling, also in the presence or absence of EDA and EDB domains, since we observed that adhesion of endothelial cells to TNC triggered counter regulatory signaling events through these two integrins. With an added focus on signaling via extracellular phosphorylation and how this impacts integrin signaling, selected point mutations in a5, a9 and ß1 will be made to eliminate the residues that were reported in the literature to be phosphorylated in the extracellular domains of integrins.Aim 3: Investigate the translation of ECM signals to nuclear events with a focus on MKL1 and YAP signaling as major molecular mechanisms that respond to actin cytoskeletal tension and dynamics that are inhibited by TNC (our unpublished results), whereas they are stimulated by adhesion to FN.Aim 4: Address in different cellular in vitro (cell derived matrices, endothelial/fibroblast cocultures as described above) and in ex vivo (aortic ring) models the impact of relevant signaling (e.g. YAP, Rho, TGFß) in a defined TNC context on sprouting angiogenesis and fibrotic responses. Why is this collaboration essential? The lack of understanding the underpinning mechanisms that drive fibrotic tissue formation poses a major medical challenge. The problem is far too big to be solved by one laboratory alone: it requires not only excellent basic sciences, but also transdisciplinary expertise and technologies, including in cell biology, molecular biology, mechanobiology, and nanotechnology, as well as state of the art imaging techniques. These are skills that our team combines, particularly in the fields of extracellular matrix (mechano)biology and integrins.
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