Elisabetta Dejana
e-mail: elisabetta.dejana AT ifom.eu
affiliation: IFOM-IEO Campus-Universita' di Milano
research area(s): Developmental Biology, Cancer Biology
Course:
Molecular Medicine: Molecular Oncology and Computational Biology
University/Istitution: Università di Milano, UNIMI-SEMM
University/Istitution: Università di Milano, UNIMI-SEMM
Research Activity:
1992-95 Chief of INSERM Unit 217, CEA Lab Hematologie, CENG, Grenoble, France
1988-03 Chief of Vascular Biology Lab, Mario Negri Institute,Milan Italy
2000- Chief of Angiogenesis Program, FIRC Institute of Molecular Oncology, Milan, Italy
Academic and Teaching Appointments:
1997 Professor at Stockholm Univ. Dept. Neurochem., Faculty of Natural Sciences. Sweden
1998-2002 Associate Professor of General Pathology at University of Insubria, School of
Medicine, Varese, Italy
Since 2002 Full professor of General Pathology of University of Milan, School of Sciences,Milan, Italy
Since 2007 Coordinator of the School of Molecular Medicine (SEMM) IFOM-IEO Campus, Milan, Italy
Awards and Honors
1996 Prize of the International Society for Thrombosis and Haemostasis, Paris, France
1997 Wennegren Foundation Award, Stockholm,Sweden
1999 John Hopkins Award in Lung Vascular Biology, Baltimore, 1999,US
2002 Ufficiale of Italian Republic, Rome,Italy
2007 William Harvey Outstanding Contribution to Science, Award 2007, London,UK
2007 Premio Speciale Donna, Pesaro,Italy
2009 Member to the Academy of Europe
2010 Laurea Honoris Causae in Medicine, University of Helsinki, Finland
Editorial tasks:
Editorial Board: The Journal of Cell Biology, EMBO Journal, EMBO reports, EMBO Medicine, BBA Cancer Reviews, American Journal of Physiology, Cell and Tissue Research, Atherosclerosis Thrombosis and Vascular Biology (2000-2004)
Solicited reviewer of grants: AICR ( International Association for Cancer Research), INSERM France, EMBO, Dutch Heart Foundation, Weizmann Institute, European Community Biomed programs, Human Frontiers Science Program, Welcome Trust UK, Medical Research Council (MRC) UK, Swiss National Science Foundation, Italian Ministry of Health, Italian Helath Institute, Italian Ministry of University and Research.
Participation in scientific advisory boards:
2001-02 Italian Ministry of Health, Scientific Advisory Committee, IRCCS
2001-03 Italian National Institute Health, National program on Stem Cell Research
Since 2002 Member of the European Molecular Biology Organization (EMBO)
Since 2002 UNESCO, Member of Natural Sciences Committee, Rome, Italy
Since 2007 International Human Fronteers Science Program Organization, Review Committee
2005-07 Scientific Advisory Board, Int Cancer Research Program, Biomedicum, Helsinki, Finland
2005-07 The Giovanni Armenise Harvard Foundation, Advisory Committee (ISAC), Rome, Italy
Since 2007 Scientific Advisory Board, Center for Transgene Technology(VIB) Univ of Leuven Belgium
Since 2008 Conseil Scientifique, Fondation Bettencourt Schueller, Paris, France
Since 2007 Scientific Advisory Board, William Harvey Research Institute, London, UK
Scientific profile
Elisabetta Dejana currently directs a research group that studies the mechanisms which regulate the development and specification of the vascular system. During her research activity ED made important contributions on different areas of vascular biology which include the response of endothelial cells to inflammatory stimuli and modulation of leukocyte traffic, characterization of the adhesion proteins which promote endothelial cell adhesion to extracellular matrix and the characterization of the architecture of endothelial cell to cell junctions with the discovery of two novel adhesion proteins specific of cell to cell junctions.
ED defined some of the pathways through which endothelial cells communicate one to another to maintain vascular integrity. She found that through cell to cell adherens junctions and, in particular, VE (vascular endothelial) cadherin and "-catenin complex, endothelial cells transfer intracellular signals which inhibit cell growth, apoptosis and establish cell polarity. These signals include: i) modulation of Vascular Endothelial Receptor2 (VEGFR2) and Transforming Growth Factor" receptor complex internalization and signaling; ii) the localization at cell to cell junctions of the polarity complex ( Par-3/PAR-6 and aPKC) which modulates endothelial polarity and vascular lumen formation; iii) the transcriptional regulation of endothelial cell differentiation and stability through FOXO1 and "-catenin complex. From these last studies she moved on to investigate more deeply the role of "-catenin and canonical Wnt signaling in vascular endothelial cells. In this particular field she made seminal discoveries on the role of canonic Wnt pathway in modulating different steps of endothelial cell differentiation in the embryo. More recently, she found that Wnt signaling mediates the induction of blood brain barrier characteristics in brain microvasculature. This last discovery opens novel pharmacological and therapeutic possibilities to control of blood brain barrier permeability to drugs or to reduce brain edema after stroke.
One of the most innovative aspects of anti-cancer therapies concerns the possibility of inhibiting tumor growth by blocking blood supply. If starved, a tumor will not grow, but, on the contrary, will shrink and become more susceptible to chemotherapy and radiotherapy. Our research is aimed at understanding the mechanisms that regulate the formation of the vascular system in tumors in order to induce their regression. A large body of information derives from the study of embryonic development, since embryo and tumor vascularization are often regulated by the same molecular mechanisms.
Project 1: The role of adhesion proteins at endothelial junctions in angiogenesis
Project 2: Beta-catenin's role in vascular development
Project 3: Definition of new genes responsible for endothelial cell differentiation
Project 4: Vascular development studies using zebrafish
Project 1: The role of adhesion proteins at endothelial junctions in angiogenesis
Project 2: Beta-catenin's role in vascular development
Project 3: Definition of new genes responsible for endothelial cell differentiation
Project 4: Vascular development studies using zebrafish
-Cattelino, A., Liebner, S., Zanetti, A., Gallini, R., Balconi, G., Corsi, A., Bianco, P., Wolburg, H., Moore, R., Oreda, B., Kemler, R. and Dejana, E. The conditional inactivation of beta-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility. J. Cell Biol. 162, 1111-1122 2003. IF: 13.96
-Lampugnani, M. G., Zanetti, A., Corada, M., Takahashi, T., Balconi, G., Breviario, F., Orsenigo, F., Cattelino, A., Kemler, R., Daniel, T. O. and Dejana, E., Contact inhibition of VEGF-induced endothelial proliferation requires VE-cadherin, b-catenin and the phosphatase DEP-1/CD148. J Cell Biol. 161, 793-804 2003. IF: 13.96
-Liebner, S., Cattelino, A., Gallini, R., Rudini, N., Piccolo, S. and Dejana, E. "-Catenin is required for TGF"-mediated endothelial to mesenchymal transformation during heart cushion development in the mouse. J. Cell Biol. 166(3):359-67 2004 IF: 13.96
-Cera, M.R., Del Prete, A., Vecchi, A., Corada, M., Martin-Padura, I., Motoike, T., Tonetti, P., Bazzoni, G., Bernasconi, S., Sato, T. N., Mantovani A. and Dejana, E.. Increased DC trafficking to lymph nodes and contact hypersensitivity in Junctional Adhesion Molecule-A deficient mice. J.Clin Invest. 114 (5):729-38 2004 IF: 15.05
-Lampugnani, M.G., Orsenigo, F., Gagliani, M.C., Tacchetti, C. and Dejana E. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments.
J Cell Biol. 2006 Aug 14;174(4):593-604 IF: 9.598
-Taddei, A., Giampietro, C., Conti, A., Orsenigo, F., Breviario, F., Pirazzoli, V., Potente, M., Daly, C., Dimmeler, S., Dejana, E. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol. 2008;10(8):923-34. IF: 18,485
-Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, Taketo MM, von Melchner H, Plate KH, Gerhardt H, Dejana E. Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol. 2008 Nov 3;183(3):409-17. IF: 10,152
-François M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah KS, Stacker SA, Muscat GE, Achen MG, Dejana E*, Koopman P*. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008 456(7222):643-7 IF: 26,681 (*Correspondent author)
-Corada M, Nyqvist D, Orsenigo F, Caprini A, Giampietro C, Taketo MM, Iruela-Arispe ML, Adams RH, Dejana E. The Wnt /beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling Dev Cell. IF:12,88 2010;18(6):938-49.
Selected Top Research monograph (invited reviews) ( source ISI)
1. Dejana, E. Endothelial cell to cell junctions: happy together. Nat Rev Cell Biol 5:261-270 2004. IF: 26.17
2. Bazzoni, G. and Dejana, E. Endothelial cell-to-cell junctions: organization, intracellular signaling and functional role in maintaining vascular homeostasis. Physiol Rev 84(3):869-901 2004 IF: 26.53
3. Weber, C., Fraemhos, L. and Dejana, E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol. 2007 Jun;7(6):467-77 IF: 28.300
4. Dejana E, Tournier-Lasserve E, Weinstein BM. The Control of Vascular Integrity by Endothelial Cell Junctions: Molecular Basis and Pathological Implications. Dev Cell. 2009;16(2):209-221. IF:13,523.
Project Title:
Transcriptional regulation of organ specific endothelial cell differentiation
Proposal summary
The brain vasculature has evolved to protect the central nervous system from the constantly changing milieu in the blood stream. Endothelial cells of brain capillaries form the so called blood brain barrier (BBB), an active permeability barrier and transport system which allows a selective passage of nutrients from blood to the nervous tissue. The continuous cross talk of endothelial cells, pericytes and nervous cells influences many vascular functions and determines and maintains the BBB characteristics after birth. Our limited knowledge of the nature of these signals prevents effective therapy of several diseases such as hemorrhagic stroke or brain edema. Furthermore, the development of tools to reversibly �open� the barrier would strongly improve drug delivery to the brain.
In the present project we propose to tackle the problem by studying the transcriptional mechanisms which direct BBB differentiation. This strategy is based on preliminary work which shows that the cross talk between nervous cells and the endothelium is mediated by Wnt factors and downstream β-catenin transcriptional activity. The understanding of the mechanism of action of Wnt signaling on brain endothelium may yield novel strategies and tools for modulating BBB permeability.
The project is divided in three related objectives: 1) to define the mechanism of action and downstream partners of Wnt in brain angiogenesis and BBB differentiation; 2) to use this knowledge to develop an optimized BBB model in vitro and in vivo; 3) to test whether modulation of Wnt signaling may have a therapeutic impact in the regulation of BBB in pathological conditions.
The brain vasculature has evolved to protect the central nervous system from the constantly changing milieu in the blood stream. Endothelial cells of brain capillaries form the so called blood brain barrier (BBB), an active permeability barrier and transport system which allows a selective passage of nutrients from blood to the nervous tissue. The continuous cross talk of endothelial cells, pericytes and nervous cells influences many vascular functions and determines and maintains the BBB characteristics after birth. Our limited knowledge of the nature of these signals prevents effective therapy of several diseases such as hemorrhagic stroke or brain edema. Furthermore, the development of tools to reversibly �open� the barrier would strongly improve drug delivery to the brain.
In the present project we propose to tackle the problem by studying the transcriptional mechanisms which direct BBB differentiation. This strategy is based on preliminary work which shows that the cross talk between nervous cells and the endothelium is mediated by Wnt factors and downstream β-catenin transcriptional activity. The understanding of the mechanism of action of Wnt signaling on brain endothelium may yield novel strategies and tools for modulating BBB permeability.
The project is divided in three related objectives: 1) to define the mechanism of action and downstream partners of Wnt in brain angiogenesis and BBB differentiation; 2) to use this knowledge to develop an optimized BBB model in vitro and in vivo; 3) to test whether modulation of Wnt signaling may have a therapeutic impact in the regulation of BBB in pathological conditions.