Visual Universitätsmedizin Mainz

Glioblastoma multiforme: Cellular and molecular
mechamisms of malignant progression.

Team: D. Kalasauskas, M. Renovanz, B. Sprang, S. Viehweg, S. Kantelhardt, A. Gutenberg, E. Kim

PIs:    E. Kim
 
Glioblastoma multiforme (GBM) is the most common and malignant form of intrinsic brain tumours in adults. A combined treatment including post-operative radio- and chemotherapy is the standard of care for GBMs. Despite aggressive treatment schemes, the overall prognosis for patients with GBM remains poor with the median survival time of less than 18 months (ref 1). The poor effectiveness of conventional treatment modalities is explained by defects in the core signalling pathways involved in the regulation of cell survival and death in glioma cells. TP53, RB and RTK/Ras/PI-3K are the critical signaling pathways most frequently altered in GBM (ref 2). Adding a further level of complexity gliomas are comprised of different cell types of varying tumorigenic potential and sensitivity to cytotoxic therapies (refs 3-5). The identification of so-called Glioma Initiating Cells (GICs) or Brain Tumour Initiating Cells (BTICs) led to the realization that intrinsic brain tumours have a hierarchical structure with only some but not all cells within the tumour possessing the capacity to propagate tumour growth (Fig. 1) and/or repopulate the tumour after cytotoxic treatments (Fig. 2). There is an emerging consensus that targeting GICs is crucial for increasing the effectiveness of cytotoxic therapies in GBM (Fig. 3). Research in our group is focused on the molecular and cellular mechanisms underlying glioma propagation and the impact of GICs in GBM recurrence. Of particular interest is the role of the TP53 pathway. Another main research focus in our group is on novel therapeutic strategies for targeting radio- and chemoresistant GICs.

References:

 

Reardon DA, Rich JN, Friedman HS, Bigner DD. (2006) Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 24: 1253-1264

The Cancer Genome Atlas (TCGA) Research Network. (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061-1068

Ignatova, T. N., Kukekov, V. G., Laywell, E. D., Suslov, O. N., Vrionis, F. D., and Steindler, D. A. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia, 39: 193-206, 2002

Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., Henkelman, R. M., Cusimano, M. D., and Dirks, P. B. Identification of human brain tumour initiating cells. Nature, 432: 396-401, 2004

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756-760


Cooperations:

Dr. Walter Schulz-Schaeffer / Dr. Alonso Barrantes / Prof. Dr. Wolfgang Brück (Department of Neuropathology, University Medical Centre Göttingen)

Dr. Gabriela Salinas
(Transcriptome Lab, University Medical Centre Göttingen)

Stefanie Lokan / Prof. Dr. Bernd Kaina
(Institute of Toxicology, University Medical Centre Mainz)

Prof. Dr. Wolfgang Müller-Klieser
(Institute of Physiology and Pathophysiology, University Medical Centre Mainz)

Dr. Carola Hartel / Prof. Dr. Marco Durante
(GSI Helmholz Centre for Heavy Ion Research, Darmstadt)

Prof. Dr. Matthias M. Weber
(Abteilung für Endokrinologie und Stoffwechselkrankheiten, Universitätsmedizin Mainz)



Selected publications

 

Barrantes-Freer A, Kim EL, Bielanska J, Giese A, Mortensen S, Stadelmann Ch, Brück W, Schulz-Schaeffer W, Stühmer W, Pardo L. Functional membrane properties of human glioma initiating cells reveal a distinct immature phenotype resembling (but nit identical to) NG2 glia. 2013 J Neuropathol Exp Neurol 72:301-24

Teplyuk NM, Mollenhauer B, Gabriely G, Giese G, Kim E, Smolsky M, Kesari S, Krichevsky AM. MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. 2012 Neurooncology 14:689-700

Kim EL, Wüstenberg R, Schmitz-Salue Ch, Rübsam A, Warnecke G, Bücker EM, Pettkus N,  Speidel D, Rohde V, Schulz-Schaeffer W, Deppert W, Giese A. Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells. 2010 Neurooncology 12:389-400

Kantelhardt SR, Caarls W, de Vries AH, Hagen GM, Jovin TM, Schulz-Schaeffer W, Rohde V, Giese A, Arndt-Jovin DJ. Specific visualization of glioma cells in living low-grade tumor tissue. PLoS One. 2010 Jun 30;5(6):e11323

Kim EL, Giese A, Deppert W. When a guardian turns into a blackguard. 2009 Biochem Pharmacol 77:11-20

Schauff AK, Kim EL, Leppert J, Nadrowitz R, Wuestenberg R, Brockmann MA, Giese A. Inhibition of invasion-associated thromboxane synthase sensitizes experimental gliomas to gamma-radiation. 2009 J Neurooncol 91:241-9

Kantelhardt S, Leppert J, Petkus N, Reusche E, Hüttmann G, Tronnier V, Giese A.  Imaging of brain and brain tumor specimens by time-resolved multiphoton excitation microscopy ex vivo. 2007. Neuro-Oncology 9:103-112

Kim EL, Deppert W. Interactions of mutant p53 with DNA: guilt by association. 2007 Oncogene 26:2185-2190

Kim EL, Deppert W. (2006). The versatile interactions of p53 with DNA: When flexibility serves specificity. Cell Death Differ 13:885-889

Walter K, Warnecke G, Bowater R, Deppert W, Kim EL. Tumor suppressor  p53 binds with high affinity to CTG:CAG repeats and induces topological alterations in mismatched duplexes. 2005 J Biol Chem 280:42497-42507

Hanson S, Kim EL, Deppert W. Redox factor 1 (Ref 1) enhances specific DNA binding of p53 by promoting p53 tetramerization. 2005 Oncogene 24:1641-1647

Göhler T, Jäger S, Warnecke G, Yasuda H, Kim EL, Deppert W. Mutant p53 proteins bind DNA in a DNA structure-selective mode. 2005 Nucl Acids Res 33:1087-1100

Kim EL, Yoshizato K, Zapf S, Kluwe L, Westphal M., Deppert W, Giese A. Functional characterization of the p53 pathway in glioma-derived cells. 2005 Anti-Cancer Res 25: 231-224

Jantke J, Kim EL, Kürzel F, Zapf S, Giese A. Inhibition of the arachidonic acid metabolism blocks endothelial cell migration and induces apoptosis. 2004 Acta Neurochirurgica 146:483-494

Kim EL, Deppert W. Transcriptional activites of mutant p53 proteins: When mutation is more than a loss. 2004 J Cell Biochem 93: 878-886

Wölke J, Reimann M, Klumpp M., Göhler T, Kim EL, Deppert W. Analysis of p53 „latency“ and „activation“ by Fluorescence Correlation Spectroscopy: Evidence for different modes of high affinity DNA binding. 2003 J Biol Chem 278: 32587-32595

Kim EL, Günther W, Yoshizato K, Meissner H, Zapf S, Nusing RM, Yamamoto H, van Meier E, Deppert W, Giese A. Tumor suppressor p53 inhibits transcriptional activation of the invasion gene thromboxane synthase mediated by the proto-oncogneic factor Ets-1. 2003 Oncogene 22: 7716-7727

Giese A, Bjerkvig R, Berens ME, Westphal M.  -The cost of Migration- Invasion of malignant Gliomas and Implications for Treatment. 2003. Journal of Clinical Oncology 21:1624-1636.



Fig. 1. Intratumoural heterogeneity and hierarchic organization of GBM.
Fig. 1. Intratumoural heterogeneity and hierarchic organization of GBM.
Fig. 3. Targeting stem cell-like GICs as a strategy for improving the efficacy of GBM therapy.
Fig. 3. Targeting stem cell-like GICs as a strategy for improving the efficacy of GBM therapy.
Fig. 2. The proposed role of stem cell-like GICs in promoting GBM recurrence.
Fig. 2. The proposed role of stem cell-like GICs in promoting GBM recurrence.

AG Molekulargenetik von Hirneigenen Tumoren


PI:  PD Dr. med. Angelika  Gutenberg

Research focus:

  • Chromosomale Aberrationen von Primärtumoren, Rezidiven und ihr Einfluss auf das Überleben
  • Zytogenetische Veränderung in der malignen Progression von Astrozytomen WHO II-IV.
  • Klinische und molekularzytogenetische Charakterisierung von Tumoren der Pinealisregion   


References:

  1. WHO blue book

 

Kooperationen:

Dr. med. Hans-Christoph Bock

Neurochirurgische Klinik, Universitätsmedizin Göttingen

Prof. Dr. med. Wolfgang Brück
Abt. Neuropathologie, Universitätsmedizin Göttingen
 


Publikationen:

 

Gutenberg A, Hong B, Enders C, Gunawan B, Schaefer IM, Burger R, Rohde V, Brandis A, Ostertag H, Gaab M, Krauss JK, Füzesi L: Common molecular cytogenetic pathway in papillary tumors of the pineal region (PTPR). Brain Pathology, 2011, 21: 672-7.

Gutenberg A, Schulten HJ, Gunawan BM, Ludwig HC, Brück W, Larsen J, Rohde V: CNS tumor 22 years after spinal neuroblastoma IV: diagnostic dilemma between recurrence and secondary malignancy. Pediatric Neurosurgery, 2009, 45: 61-8.  

Yakut T, Gutenberg A, Bekar A, Egeli U, Gunawan B, Ercan I, Tolunay S, Doygun M, Schulten HJ: Correlation of chromosomal imbalances by comparative genomic hybridization and expression of EGFR, PTEN, p53, and MIB-1 in diffuse gliomas. Oncology Reports, 2007, 17: 1037-43.