Interplay of integrin-mediated adhension and MMP14-driven proteolysis in matrix barrier-breaking invadopodia of tumour cells

    The molecular linkage between b1 integrins and MMP14 within invadopodia of melanoma cells will be disclosed at protein-chemical and cellular level. To study their functional linkage, integrin-dependent localization and activity of MMP14 within invadopodia will be analyzed. Inhibition of melanoma invasion by individually targeting MMP14 will be compared with an approach of dual targeting both b1 integrins and MMP14 with novel bifunctional integrin- and MMP14-targeting (BIMT) molecules at the cellular level. Translationally, BIMTs will be tested for their potential to inhibit melanoma invasion in chicken CAM and murine lung assay.

    Research areas: Vascular Matrix Biology, Integrin-Matrix Interaction, Protein Chemistry

    Prof. Dr. rer. nat. Johannes Eble

    Funding periodt: January 2014 - June 2020

    • Publications

      Original articles

      • Rezaei M, Martins Cavaco AC, Seebach J, Niland S, Zimmermann J, Hanschmann EM, Hallmann R, Schillers H, Eble JA (2019) Signals of the neuropilin-1-MET axis and cues of mechanical force exertion converge to elicit inflammatory activation in coherent endothelial cells. J Immunol 202: 1559-1572.
      • Cavaco ACM, Rezaei M, Caliandro MF, Lima AM, Stehling M, Dhayat SA, Haier J, Brakebusch C, Eble JA (2018) The Interaction between laminin-332 and ?3?1 Integrin determines differentiation and main-tenance of CAFs, and supports invasion of pancreatic duct adenocarcinoma cells. Cancers (Basel) 11: 14.
      • Lima AM, Wegner SV, Martins Cavaco AC, Estevao-Costa MI, Sanz-Soler R, Niland S, Nosov G, Klingauf J, Spatz JP, Eble JA (2018) The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine alpha2beta1 integrin-dependent platelet activation. Biomaterials 167: 107-120.
      • Niland S, Komljenovic D, Macas J, Bracht T, Bauerle T, Liebner S, Eble JA (2018) Rhodocetin-?? selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models. Oncotarget 9: 22406-22422.
      • Woltersdorf C, Bonk M, Leitinger B, Huhtala M, Kapyla J, Heino J, Gil Girol C, Niland S, Eble JA, Bruckner P, Dreier R, Hansen U (2017) The binding capacity of alpha1beta1-, alpha2beta1- and alpha10beta1-integrins depends on non-collagenous surface macromolecules rather than the collagens in cartilage fibrils. Matrix Biol: 91-105.
      • Eble JA, McDougall M, Orriss GL, Niland S, Johanningmeier B, Pohlentz G, Meier M, Karrasch S, Estevao-Costa MI, Martins Lima A, Stetefeld J (2017) Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively. PLoS Biol 15: e2001492.
      • Jakobs P, Schulz P, Schurmann S, Niland S, Exner S, Rebollido-Rios R, Manikowski D, Hoffmann D, Seidler DG, Grobe K (2017) Calcium coordination controls sonic hedgehog structure and Scube2-cubulin domain regulated release. J Cell Sci., in press.
      • Ghatak S, Niland S, Schulz JN, Wang F, Eble JA, Leitges M, Mauch C, Krieg T, Zigrino P, Eckes B (2016) Role of Integrins alpha1beta1 and alpha2beta1 in Wound and Tumor Angiogenesis in Mice. Am J Pathol 186(11): 3011-3027. (doi: 10.1016/j.ajpath.2016.06.021. Epub 2016 Sep 14) 
      • Pelillo C, Mollica H, Eble JA, Grosche J, Herzog L, Codan B, Sava G, Bergamo A (2016) Inhibition of adhesion, migration and of alpha5beta1 integrin in the HCT-116 colorectal cancer cells treated with the ruthenium drug NAMI-A. J Inorg Biochem 160: 225-235. (doi: 10.1016/j.jinorgbio.2016.02.025. Epub 2016 Feb 27.) 
      • Sanchez EF, Richardson M, Gremski LH, Veiga SS, Yarleque A, Niland S, Lima AM, Estevao-Costa MI, Eble JA(2016) A novel fibrinolytic metalloproteinase, barnettlysin-I from Bothrops barnetti (barnett s pitviper) snake venom with anti-platelet properties. Biochim Biophys Acta 1860: 542-556. 
      • Sanchez EF, Richardson M, Gremski LH, Veiga SS, Yarleque A, Niland S, Lima AM, Estevao-Costa MI, Eble JA(2016) Data for a direct fibrinolytic metalloproteinase, barnettlysin-I from Bothrops barnetti (barnett(,)s pitviper) snake venom with anti-thrombotic effect. Data Brief 7: 1609-1613. 
      • Baldo C, Lopes DS, Faquim-Mauro EL, Jacysyn JF, Niland S, Eble JA, Clissa PB, Moura-da-Silva AM (2015) Jararhagin disruption of endothelial cell anchorage is enhanced in collagen enriched matrices. Toxicon, in press [doi 10.1016/j.toxicon.2015.10.016].
      • Momic T, Katzhendler J, Shai E, Noy E, Senderowitz H, Eble JA, Marcinkiewicz C, Varon D, Lazarovici P (2015) Vipegitide: A folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity. Drug Des Devel Ther 9: 291-304.
      • Bolas G, de Rezende FF, Lorente C, Sanz L, Eble JA, Calvete JJ (2014) Inhibitory effects of recombinant RTS-jerdostatin on integrin α1β1 function during adhesion, migration and proliferation of rat aortic smooth muscle cells and angiogenesis. Toxicon 79: 45-54.
      • Momic T, Katzehendler J, Benny O, Lahiani A, Cohen G, Noy E, Senderowitz H, Eble JA, Marcinkiewicz C, Lazarovici P (2014) Vimocin and vidapin, cyclic KTS peptides, are dual antagonists of α1β1/α2β1 integrins with antiangiogenic activity. J Pharmacol Exp Ther 350: 506-519.
      • Musumeci L, Kuijpers MJ, Gilio K, Hego A, Théâtre E, Maurissen L, Vandereyken M, Diogo CV, Lecut C, Guilmain W, Bobkova EV, Rascon J, Eble JA, Dahl R, Drion P, Mostofi Y, Yuan H, Sergienko E, Chung TD, Thiry M, Senis Y, Moutschen M, Mustelin T, Lancellotti P, Heemskerk JW, Tautz L, Oury C, Rahmouni S (2014) DUSP3 phosphatase deficiency or inhibition limit platelet activation and arterial thrombosis. Circulation (in press). [CIRCULATIONAHA.114.010186. Epub ahead of print]
      • Michaelis UR, Chavakis E, Kruse C, Jungblut B, Kaluza D, Wandzioch K, Manavski Y, Heide H, Santoni MJ, Potente M, Eble JA, Borg JP, Brandes RP (2013) The polarity protein Scrib is essential for directed endothelial cell migration. Circ Res 112: 924-934.
      • Nikolic I, Stankovic ND, Bicker F, Meister J, Braun H, Awwad K, Baumgart J, Simon K, Thal SC, Patra C, Harter PN, Plate KH, Engel FB, Dimmeler S, Eble JA, Mittelbronn M, Schafer MK, Jungblut B, Chavakis E, Fleming I, Schmidt MH (2013) EGFL7 ligates αvβ3 integrin to enhance vessel formation. Blood 121: 3041-3050.
      • Niland S, Ditkowski B, Parrandier D, Roth L, Augustin H, Eble JA (2013) Rhodocetin-αβ-induced neuropilin-1-cMet association triggers restructuring of matrix contacts in endothelial cells. Arterioscler Thromb Vasc Biol 33: 544-554.
      • Kusuma N, Denoyer D, Eble JA, Redvers RP, Parker BS, Pelzer R, Anderson RL, Pouliot N (2012) Integrindependent response to laminin-511 regulates breast tumor cell invasion and metastasis. Int J Cancer 130: 555-566.
      • Niland S, Eble JA (2012) Integrin-mediated cell-matrix interaction in physiological and pathological blood vessel formation. J Oncol 2012: 125278.