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Neue matrizelluläre Moleküle beteiligt bei Angiogenese und vaskulären Erkrankungen

English title Novel Matricellular Molecules in Angiogenesis and Vascular Diseases
Applicant Imhof Beat A.
Number 153456
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Cancer Research
Start/End 01.04.2014 - 30.09.2017
Approved amount 678'000.00
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Keywords (5)

angiogenesis; pericytes; vascular endothelium; extracellular matrix; tumor biology

Lay Summary (German)

Lead
Therapien gegen Krebserkrankungen zielen entweder direkt auf die Krebszellen oder sie verhindern die Bildung des Blutgefässsystems das den Tumor mit Nahrungsstoffen versorgt. Letzteres ist vielversprechend da es im Prinzip für viele Tumorarten anwendbar ist, führt aber mit den aktuell verwendeten Methoden zu unerwünschten Nebenwirkungen. Wir haben ein neues Molekül entdeckt Olfactomedin-like 3 (Olfml3), das in der unmittelbaren Umgebung von Tumorgefässen für deren Wachstum und Entwicklung notwendig ist. Hemmung dieses Moleküls könnte Krebstherapien verbessern.
Lay summary

Neue Blutgefässe entstehen durch Aussprossung von Endothelzellen aus bestehenden Gefässen, wenn diese Wachstumsfaktoren ausgesetzt werden. Dabei bilden Endothelzellen neue, schlauchähnliche Gefässe, die dann von sogenannten Perizyten stabilisiert werden. Unser Olfml3 bindet den vaskulären Wachstumsfaktor BMP4 und präsentiert  diesen den Blutgefässen in Tumoren. Wir werden versuchen, diese Präsentation mittels sogenannten monoklonalen Antikörpern zu verhindern, solche wurden von unserem Labor bereits produziert. Dies  versuchen wir mit in vitro Zellsystemen und im Tierexperiment zu zeigen. Dabei werden verschiedene Tumorarten eingesetzt. Ferner werden wir eine Maus untersuchen, die defekt für das Olfml3 Gen ist. Und schliesslich möchten wir die Signale untersuchen, die von dem Komplex Olfml3/BMP4 in Endothelzellen ausgelöst werden. Ferner untersuchen wir die Rolle von Olfml3 in der Interaktion von Perizyten mit dem Endothel.  Für das Funktionieren eines Blutgefässes scheint dies von imminenter Bedeutung zu sein.

 

 

 

Direct link to Lay Summary Last update: 27.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
New treatment for non-Hodgkin B-cell lymphomas with a special focus on the impact of junctional adhesion molecules
Imhof B.A., Matthes T. (2017), New treatment for non-Hodgkin B-cell lymphomas with a special focus on the impact of junctional adhesion molecules, in Swiss Med Wkly, 147, w14487.
Toll-like receptors elicit different recruitment kinetics of monocytes and neutrophils in mouse acute inflammation
Imhof B.A., Jemelin S., Emre Y. (2017), Toll-like receptors elicit different recruitment kinetics of monocytes and neutrophils in mouse acute inflammation, in Eur J Immunol, 47(6), 1002-1008.
Biodegradable and plasma-treated electrospun scaffolds coated with recombinant Olfactomedin-like 3 for accelerating wound healing and tissue regeneration
Dunn L.L., de Valence S., Tille J.C., Hammel P, WlapothB.H., Stocker R., Imhof B.A., Miljkovic-Licina M. (2016), Biodegradable and plasma-treated electrospun scaffolds coated with recombinant Olfactomedin-like 3 for accelerating wound healing and tissue regeneration, in Wound Repair Regen, 24(6), 1030-1035.
Anti-JAM-C therapy eliminates tumor engraftment in a xenograft model of mantle cell lymphoma
Donate C, Vijaya Kumar A., Imhof B.A., Mathes T. (2016), Anti-JAM-C therapy eliminates tumor engraftment in a xenograft model of mantle cell lymphoma, in J Leukoc Biol, 100(5), 843-853.
Aortic aneurysm, CCN3 may solve the problem.
Emre Yalin, Imhof Beat A (2016), Aortic aneurysm, CCN3 may solve the problem., in Journal of thoracic disease, 8(9), 1025-1027.
CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation.
Imhof Beat A, Jemelin Stephane, Ballet Romain, Vesin Christian, Schapira Marco, Karaca Melis, Emre Yalin (2016), CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation., in Proceedings of the National Academy of Sciences of the United States of America, 113(33), 4847-56.
Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques.
Bradfield Paul F, Menon Arjun, Miljkovic-Licina Marijana, Lee Boris P, Fischer Nicolas, Fish Richard J, Kwak Brenda, Fisher Edward A, Imhof Beat A (2016), Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques., in PloS one, 11(7), 0159679-0159679.
Élie Metchnikoff (1845-1916): celebrating 100 years of cellular immunology and beyond.
Underhill David M, Gordon Siamon, Imhof Beat A, Núñez Gabriel, Bousso Philippe (2016), Élie Metchnikoff (1845-1916): celebrating 100 years of cellular immunology and beyond., in Nature reviews. Immunology, 16(10), 651-6.
Reverse Migration of Neutrophils: Where, When, How, and Why?
Nourshargh Sussan, Renshaw Stephen A, Imhof Beat A (2016), Reverse Migration of Neutrophils: Where, When, How, and Why?, in Trends in immunology, 37(5), 273-86.
Endothelial-specific deficiency of Junctional Adhesion Molecule-C promotes vessel normalisation in proliferative retinopathy.
Economopoulou Matina, Avramovic Nemanja, Klotzsche-von Ameln Anne, Korovina Irina, Sprott David, Samus Maryna, Gercken Bettina, Troullinaki Maria, Grossklaus Sylvia, Funk Richard H, Li Xuri, Imhof Beat A, Orlova Valeria V, Chavakis Triantafyllos (2015), Endothelial-specific deficiency of Junctional Adhesion Molecule-C promotes vessel normalisation in proliferative retinopathy., in Thrombosis and haemostasis, 114(6), 1241-9.
Functional role of a polymorphism in the Pannexin1 gene in collagen-induced platelet aggregation.
Molica F, Morel S, Meens M J, Denis J-F, Bradfield P F, Penuela S, Zufferey A, Monyer H, Imhof B A, Chanson M, Laird D W, Fontana P, Kwak B R (2015), Functional role of a polymorphism in the Pannexin1 gene in collagen-induced platelet aggregation., in Thrombosis and haemostasis, 114(2), 325-36.
Junctional adhesion molecule B interferes with angiogenic VEGF/VEGFR2 signaling.
Meguenani Mehdi, Miljkovic-Licina Marijana, Fagiani Ernesta, Ropraz Patricia, Hammel Philippe, Aurrand-Lions Michel, Adams Ralf H, Christofori Gerhard, Imhof Beat A, Garrido-Urbani Sarah (2015), Junctional adhesion molecule B interferes with angiogenic VEGF/VEGFR2 signaling., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 29(8), 3411-25.
Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo.
Colom Bartomeu, Bodkin Jennifer V, Beyrau Martina, Woodfin Abigail, Ody Christiane, Rourke Claire, Chavakis Triantafyllos, Brohi Karim, Imhof Beat A, Nourshargh Sussan (2015), Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo., in Immunity, 42(6), 1075-86.
Blocking junctional adhesion molecule C enhances dendritic cell migration and boosts the immune responses against Leishmania major.
Ballet Romain, Emre Yalin, Jemelin Stéphane, Charmoy Mélanie, Tacchini-Cottier Fabienne, Imhof Beat A (2014), Blocking junctional adhesion molecule C enhances dendritic cell migration and boosts the immune responses against Leishmania major., in PLoS pathogens, 10(12), 1004550-1004550.
Matricellular protein CCN1/CYR61: a new player in inflammation and leukocyte trafficking.
Emre Yalin, Imhof Beat A (2014), Matricellular protein CCN1/CYR61: a new player in inflammation and leukocyte trafficking., in Seminars in immunopathology, 36(2), 253-9.
Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours
Sidibé A., Ropraz P., Jemelin S., Emre Y., Poittevin M., Pocard M., Bradfield P., Imhof B, Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours, in Nature Comm.

Associated projects

Number Title Start Funding scheme
135701 Junctional adhesion molecules, versatile players in inflammatory immune reactions 01.04.2011 Project funding

Abstract

Most cancer therapies are directed against tumor cells, however a growing number of cancer therapeutics target cells of the tumor microenvironment. Antiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of the limited efficacy of current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. We have recently identified Olfactomedin-like 3 (Olfml3) as a novel matricellular cue within the tumor microenvironment, which exhibits proangiogenic properties. Similarly to other matricellular proteins, Olfml3 is highly expressed during development, whilst its expression in the adult is limited largely to tissues undergoing normal or pathological remodeling. In addition,Olfml3-/- mice are viable and exhibit no overt vascular morphogenetic defects, suggesting that Olfml3 isdispensable for normal embryogenesis like most matricellular proteins. Finally, our recent study has demonstrated the ability of Olfml3 to regulate adult vascular remodeling under normal or pathological conditions e.g. tumor angiogenesis. We have shown that tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes, and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelial cell migration and sprouting. Moreover, Olfml3 has been previously described as an extracellular modulator of bone morphogenetic protein (BMP) signaling. We have demonstrated that both mouse and human homologues of Olfml3 interact with BMP4, which has been characterized as a potent pro-angiogenic factor. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis.As an integral part of the experiments proposed in this grant application, we aim to dissect the role of Olfml3 in the alternative mechanisms that regulate the formation of blood vessels within solid tumors. A prerequisite for these studies will be elucidating the role of Olfml3 in cell-matrix and cell-cell communications and how these are influenced by e.g. microRNAs and/or growth factors like BMP4. Experiments orientated towards understanding the signal transduction cascade mediated by Olfml3 and how this can influence gene expression and cell behavior are also considered high priority. Further studies are needed to determine if blocking Olfml3 will be a more effective strategy in controlling tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule. If pericytes are also identified as a target for tumor therapy, it becomes important to map the molecular mechanism involved in pericyte recruitment to the tumor vessel wall. For this reason, one of the objectives of this grant proposal is to clarify the regulatory role of Olfml3 in endothelial-pericyte crosstalk. We also plan to explore the potential role of Olfml3 in atherosclerosis. Consistent with this approach, our broader focus will remain at translating the rapidly expanding knowledge base of the matricellular protein family into a clinical setting. This will be done by identifying promising drug targets and defining new therapeutic strategies to treat vascular and malignant disorders.
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