Post on 08-Mar-2018
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Research Cluster #5
Microenvironment, Vasculature & Metastasis
CoordinatorsMedhat Shehata / Dontscho Kerjaschki
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
A complex topic which offers many therapeutic targets
Adhesion
MoleculesIntegrins signaling
Matrix
component:Collagen, Fibronectin, Hyaluronan, Other matrix proteins
Soluble component:Cytokines, Chemokines, Growth factors
Cellular
component:B, T, NK cells Macrophages, DC, ECStromal cells, adipocytes
Cell motilty, migrarion &Drug resistance
Oncogenesis & Epithelial/mesenchymal transition
Angiogenesis&Lymph-angiogenesis
Tumor escape, Shedding, circulation &dissemination
Microenvironment, Vasculature & Metastasis
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Leukemia and solid tumor models & interconnection
LSC
EC EC
LCLSC
SC
Leukemia model
SC/TAF
TSC
TC
TSC
Solid tumor model
Tumor initiation, expansion, recirculation,origin, stem cells
Metastasis, dissemination,angiogenesis, lymphangiogenesis
CTC/DTC,Marrow micrometastasis
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Participants, Departments & Institutes
1. Institut für Krebsforschung2. Universitätsklinik für Innere Med I: 3. Universitätsklinik für Innere Med II 4. Universitätsklinik für Innere Med III5. Klinisches Institut für Pathologie6. Universitätsklinik für Dermatologie7. Universitätsklinik für Blutgruppenserologie &
Transfusionmedizin8. Klinische Inst. Für Medizinische &
Chemische Labordiagnostik9. Universitätsklinik für Strahlentherapie10. Universitätsklinik für Chirurgie11. Universitätsklinik für Frauenheilkunde12. Institut für Pharmakologie13. CeMM - Centrum für molekulare Medizin14. St. Anna Kinderspital15. The Max F. Perutz Laboratories (MFPL)16. Institute of pharmacology and toxicology:17. University of Veterinary Medicine Vienna, VMW
- Registered participants: 65
- Clinicians &Basic Researchers
- 17 institutes
- Regular meetings: 2 times a year
- Working groups meetings: frequent
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Projects submitted by
members of the cluster
1- P. Petzelbauer: Wiener Wissenschafts-, Forschungs- und Technologiefonds 2011-2014 (LS11-008) 4-P.
2. Petzelbauer: FWF 2011-2014 (P24022-B21)3. Kerjaschki: TranSVIR - Translational Science for Vascular Inflammation and Remodelling (EU,
Project ID 238756; MUW: 1009k, 2009-2013)4. Kerjaschki: E-Rare – Epidermal growth factor system in rare glomerular disease (EU/FWF,
Project ID. I923-B13; MUW 157k, 2012-2014)5. W. Mikulits: EU-Project “IT-LIVER” FP7-PEOPLE-2012-ITN6. Shehata/Gerner: Secretome and proteom analysis of CLL microenvironment. IK-Forschung7. Shehata/ Holtzmann: Mesenchymal stem cells and telomerase. IK-Forschung8. M. Schreiber: Hallmarks of epithelial-mesenchymal transition in a panel of clinical human
breast cancer samples; Martin Schreiber; ÖNB; decision pending9. M. Schreiber: The role of a common polymorphism in the cyclooxygenase-2 promotor in breast
cancer; Katharina Tomek; DOCfforte of the Austrian academy of science; not funded10. Shehata/ Kerjaschki: CTC/DTC: CCC grant proposal: not funded11. Ch. Brostjan/E Hofer: NK cells: CCC grant proposal: not funded
More than 10 projects have been submitted, funded or bending
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
International & national academic cooperation
1. Petzelbauer/Erwin Wagner, Madrid, 2. Petzelbauer/Sandra Citi, Geneva, 3. Petzelbauer/Marcus Schultz, Amsterdam4. Petzelbauer/Kai Zacharowski, Frankfurt5. Kerjaschki / Prof V Sexl (VetMed); Kerjaschki / Prof M Swartz (ETH Lausanne)6. W. Mikulits: FWF-SFB “Jak-Stat”, "RESOLVE Chronic Inflammation and Achieve
Healthy Aging by Understanding Non-regenerative Repair. - Proj.Nr.: HEALTH-F4-2008-202047"
7. Shehata/J. Burger MD Anderson USA: CLL microenvironment8. Shehata/J. Burger MD Anderson USA: ALL/CXCR4 M. Schreiber: Membership and
cooperations within cluster 6 and 7. 9. M. Shehata/J. Vasicek: Slovak republic: hematopoietic stem cells 10. C. Brostjan/ collaboration with Cluster #4: Prof. Mac Felda and Markus Mandl11. M. Schreiber: Cooperations with other scientists at MUW, IMP and IMBA12. Proteome and secretome analysis M. Shehata/C. Gerner13. Mesenchymal Stem cells-Telomerase: M. Shehata/K. Holzmann 14. Shehata, Kerjaschki, DTC/CTC : 7 clusters, CCC grant application
At least 14 international coperation projects and exchange program between the research clusters have been initiated
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Cluster Database for exchangeof knowledge and materials (planned)
Activities
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Selected Projects / Publications>32 papers: 198,4 IF>10 papers, CCC cited: 78,3 IF
1. Identification of a rational and highly effective therapy to treat NPM-ALKdriven lymphomas Daniela Laimer Daniela Laimer, Helmut Dolznig, Karoline Kollmann, Paul W. Vesely, Michaela Schlederer, Olaf Merkel, Ana-Iris Schiefer,Melanie R. Hassler, Susi Heider, Lena Amenitsch, Christiane Thallinger, Philipp B. Staber, Ingrid Simonitsch-Klupp,Matthias Artaker, Stefano Pileri, Pier Paolo Piccaluga, Peter Valent, Katia Messana, Indira Landra, Thomas Weichhart,Sylvia Knapp, Medhat Shehata, Maria, Veronika Sexl, Gerald Höfler, Roberto Piva, Enzo Medico, Gerda Egger, Josef M. Penninger, Ulrich Jaeger,Richard Morigg, Giorgio Inghirami and Lukas Kenner (Re-submitted to Nature).
2. Lipoxygenase mediates invasion of intrametastatic lymphatic vesselsand propagates lymph node metastasis of human mammary carcinomaxenografts in mouse. Zsuzsanna Bago-Horvath, Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S, Bartel G, Krieger S, Kalt R, HantuschB, Keller T, Nagy-Bojarszky K, Huttary N, Raab I, Lackner K, Krautgasser K, Schachner H, Kaserer K, Rezar S, Madlener S, Vonach C, Davidovits A, Nosaka H, Hämmerle M, Viola K, Dolznig H, Schreiber M, Nader A, Mikulits W,Gnant M, Hirakawa S, Detmar M, Alitalo K, Nijman S, Offner F, Maier TJ, Steinhilber D, Krupitza G. (2011). The Journalof Clinical Investigation 121, 2000- 2012. IF: 14.152 (CCC cited)
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Identification of a rational and highly effective therapyto treat NPM-ALK driven
lymphomas Mag. Daniela Laimer
Clinical Institute of Pathology, Medical University of Vienna
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
NPM-ALKJun mice survive 75% longer than control mice
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
PDGFRβ is a novel direct AP-1 target, blockage significantly lowers tumor size in vivo
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Blockage of PDGFRβ in a terminal human NPM-ALK positive ALCL patient lead to full remission
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Model
FOLIEN TEXT
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Acknowledgements
Gerald Höfler,
Paul Vesely,
Phillipp Staber,
Institute of Pathology,
Medical University of Graz
Lukas KennerGerda Egger,Michaela Schlederer Richard MorigglMelanie HasslerLena Amenitsch
Inst. of clinical Pathology, MUW/Ludwig Boltzmann Institute of Cancer Research Vienna
Josef PenningerArabella MeixnerIMBA Vienna
Christiane ThallingerMedhat ShehataUllrich Jäger1. Med. Univ. Clinic MUW
Erwin F. Wagner, CNIO Madrid
Giorgio Inghirami, Inst. Pathol. Univ. Turino
Karoline KollmannVeronika Sexl
University of Vet. Medicine, Vienna
Helmut DolznigInst. of Medical Genetics, MUW
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Mechanisms of lymph node metastasis in breast cancer
Kerjaschki et al, J Clin Invest. 2011;121(5):2000‐12.
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
GAP formation in LV by tumor cell clusters
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
N0 N1 N2/3
Ductal Carcinoma (n=76) ‐‐‐‐ 0% 100%
Lobular Carcinoma (n=37) ‐‐‐‐ 6% 58%
Intrametastatic lymphatic tumor embolization is predictive of post‐sentinel lymph node involvement
Kerjaschki et al, J Clin Invest.2011 May 2;121(5):2000‐12. doi: 10.1172/JCI44751.
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
MCF-7 spheroid induce gap formationin LEC monolayers
Kerjaschki et al, J Clin Invest.2011 May 2;121(5):2000‐12. doi: 10.1172/JCI44751.
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
15-LO knock down reducesgap formation
Kerjaschki et al, J Clin Invest.2011 May 2;121(5):2000‐12. doi: 10.1172/JCI44751.
www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Xenograft experiments
Xenografts of MCF-7 / VEGF-C cellsplus / minus 15 LOX knockdown
Kerjaschki et al, J Clin Invest.2011 May 2;121(5):2000‐12. doi: 10.1172/JCI44751.
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www.ccc.ac.at Cluster: Microenvironment, Vasculature and Metastasis
Acknowledgements
Dontscho KerjaschkiMargaretha Rudas
Georg KrupitzaBrigitte Hantusch
Michael GnantPeter DubskyRuth Exner
Kari Alitalo
Thomas Helbich
Veronika SexlChristine Schneckenleithener
Susanne WolbankMartin Schreiber
Romana KaltSigurd KriegerNicole Huttary
Ingrid RaabHelga Schachner
Karin Lackner
Thorsten MeierDieter Steinhilber