Main Field(s) of Research, Abstract
Our research group investigates the biology of malignant gliomas. These tumors, notably glioblastomas, are among the most lethal neoplasms. Gliomas are paradigmatic for their ability to deeply infiltrate the surrounding healthy tissue, precluding definitive surgical resection and limiting the efficacy of other local therapies. The results achieved with traditional cancer therapies are poor because of defects in the apoptotic machinery of glioma cells, accounting for their resistance to irradiation and chemotherapy. Putative glioma-initiating (stem) cells have been identified which display stem cell characteristics such as the capacity for self-renewal, multipotency and tumorigenicity, leading to a hierarchical model of gliomagenesis. They may also contribute to pathological angiogenesis and immune suppression in the local tumor environment.
Based on these considerations, the main interests of our laboratory include apoptosis research, tumor immunology as well as migration, invasion and angiogenesis, relating to malignant gliomas. We have established various techniques as well as different animal models to examine the key properties of glioblastoma cells in vitro and in vivo. We will continue to develop our major research platforms: (i) resistance to current standards of care including radiotherapy, chemotherapy and anti-angiogenesis, (ii) novel strategies of immunotherapy and (iii) the contribution of stem-like glioma cells to the biological properties of these tumors.
Main Fields of Research, Keywords
Glioma, apoptosis, invasion, immune escape, cancer stem cell, chemoresistance, angiogenesis
Special Techniques and Equipment
All standard methods of biochemistry, cell and molecular biology are being used in our laboratory, e.g., real-time PCR, immunoblot, apoptosis and proliferation assays, cell cycle analysis, transfection techniques, siRNA technology, and immunological assays. We also use different in vivo rodent glioma models and in vivo glioma imaging in mice.
Education and Training
We offer training opportunities for graduate, PhD and MD students interested in the research topics mentioned above as well as weekly journal clubs and project report seminars.
Weinmann L, Wischhusen J, Demma MJ, Naumann U, Roth P, DasMahapatra B, Weller M. A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 2008;15:718-729
Tabatabai G, Herrmann C, von Kürthy G, Mittelbronn M, Grau S, Frank B, Möhle R,Weller M, Wick W. VEGF-dependent induction of CD62E on endothelial cells mediates glioma tropism of adult hematopoietic progenitor cells. Brain 2008;131:2579-2595
Maurer GD, Tritschler I, Adams A, Tabatabai G, Wick W, Stupp R, Weller M. Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro. Neuro-Oncology 2009;11:747-756
Tritschler I, Gramatzki D, Capper D, Mittelbronn M, Meyermann R, Saharinen J, Wick W, Keski-Oja J, Weller M. Modulation of TGF-β activity by latent TGF-β-binding protein 1 in human malignant glioma cells. Int J Cancer 2009;125:530-540
Ronellenfitsch MW, Brucker DP, Burger MC, Wolking S, Tritschler F, Rieger J, Wick W, Weller M, Steinbach JP. Antagonism of mTOR selectively mediates metabolic effects of EGFR inhibition and protects human malignant glioma cells from hypoxia-induced cell death. Brain 2009;132:1509-1522
Opitz CA, Litzenburger UM, Lutz C, Lanz TV, Tritschler I, Köppel A, Tolosa E, Hoberg M, Anderl J, Aicher WK, Weller M, Wick W, Platten M. Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via Interferon-β and protein kinase R. Stem Cells 2009;27:909-919
Gramatzki D, Pantazis G, Schittenhelm J, Tabatabai G, Köhle C, Wick W, Schwarz M, Weller M, Tritschler I. Aryl hydrocarbon receptor inhibition down-regulates the TGF-β/smad pathway in human glioblastoma cells. Oncogene 2009;28:2593-2605
Roth P, Kissel M, Herrmann C, Eisele G, Leban J, Weller M, Schmidt F. SC68896, a novel small molecule proteasome inhibitor, exerts anti-glioma activity in vitro and in vivo. Clin Cancer Res 2009;15:6609-6618
Roth P, Junker M, Tritschler I, Mittelbronn M, Dombrowski Y, Breit SN, Tabatabai G, Wick W, Weller M, Wischhusen J. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin Cancer Res 2010;26:3851-3859
Schraivogel D, Weinmann L, Beier D, Tabatabai G, Eichner A, Zhu JY, Anton M, Sixt M, Weller M, Beier CP, Meister G. CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells. EMBO J 2011;30:4309-4322
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GG, Miller CL, Lutz C, Radlwimmer B, Lehmann I, Von Deimling A, Wolfgang Wick W, Platten M. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011;478:197-203
Hasenbach K, Wiehr S, Herrmann C, Mannheim J, Cay F, Von Kürthy G, Bolmont T, Grathwohl SA, Weller M, Lengerke C, Pichler BJ, Tabatabai G. Monitoring the glioma tropism of bone marrow-derived progenitor cells by two-photon laser scanning microscopy and positron emission tomography. Neuro-Oncology 2012;14:471-481
Lemke D, Pfenning PN, Sahm F, Klein AC, Kempf T, Warnken U, Schnölzer M, Tudoran R, Weller M, Platten M, Wick W. Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness. Clin Cancer Res 2012;18:105-117
Happold C, Roth P, Wick W, Schmidt N, Florea AM, Silginer M, Reifenberger G, Weller M. Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J Neurochem 2012;122:444–455
Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M, for the Neurooncology Working Group (NOA) of the German Cancer Society. Chemotherapy versus radiotherapy for malignant astrocytoma in the elderly. Lancet Oncol 2012;13:707-715
Wolpert F, Roth P, Lamszus K, Tabatabai G, Weller M, Eisele G. HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells. J Neuroimmunol 2012;250:27-34
Weiler M, Pfenning PN, Thiepold AL, Jestaedt L, Gronych J, Dittmann L, Berger B, Jugold M, Kosch M, Weller M, Combs SE, von Deimling A, Bendszus M, Platten M, Wick W. Suppression of invasion-driving RGS4 by radiation-enhanced mTOR inhibition optimizes antiangiogenesis. Oncogene 2013;32:1099-1109
Roth P, Silginer M, Goodman SL, Hasenbach K, Thies S, Maurer G, Schraml P, Tabatabai G, Moch H, Tritschler I, Weller M. Integrin control of the transforming growth factor-b pathway in glioblastoma. Brain 2013;136:564-576
Gramatzki D, Herrmann C, Happold C,Becker KA, Gulbins E, Weller M, Tabatabai G. Glioma cell death induced by irradiation or alkylating agent chemotherapy is independent of the intrinsic ceramide pathway. PLoS One 2013;e63527
Vogetseder A, Thies S, Ingold B, Roth P, Weller M, Schraml P, Goodman S, Moch H. αv-Integrin isoform expression in primary human tumors and brain metastases. Int J Cancer in press
Weller M, Pfister SM,Wick W, Hegi ME, Reifenberger G, Stupp R. Molecular neuro-oncology entering clinical practice: a new horizon. Lancet Oncol in press
LAST UPDATE: 2013-5-18