Molecular Mechanisms of Tumor Cell Invasion

CHS Research Group Molecular Mechanisms of Tumor Cell Invasion

Dr. Björn Tews

Real-time Cell Analysis (RTCA) of cells overexpressing a wildtype (wt) or inactive (mut) form of a sphingolipid G-protein coupled receptor which negatively regulates cell adhesion and spreading on a CNS myelin substrate. Cell Index (CI) decribes a relative change in electrical impedance representing the morphological cell status. Data shown are mean values ± SEM.
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Glioblastoma is the most aggressive brain tumor with a poor prognosis, as reflected by a median patient survival of about 14 months. The invasive nature of glioma cells mainly accounts for their resistance to current treatment modalities: the diffusely infiltrating tumor cells, which evade surgical resection and survive treatment, inevitably give rise to reoccurring tumors. We are studying three different paradigms, which mediate brain tumor invasion and resistance: (1) Alteration of the extracellular matrix by secreted glycoproteins involving the Unfolded Protein Response (UPR); (2) expression of pro-invasive endogenous driver proteins and (3) cross talk of tumor with stroma cells (e.g., microglia), which then supports tumor growth and invasion.

The invasion of the surrounding healthy brain tissues by glioma cells does not happen randomly. It has been found to be associated with distinct anatomic structures such as the basement membranes of blood vessels. With regards to migration and invasion, the inhibitory myelin pathways (Kempf and Tews et al., 2013) also serve as essential structures for glioma cell invasion. The currently used standard therapies, such as radio and alkylating chemotherapy, target dividing cells. Yet, invading cells seem to be therapy-resistant, which creates a major problem for efficient treatment. New therapeutic agents could render cells more susceptible to established therapeutic methods. In this connection, specific branches of the UPR show great potential as targets for therapeutic interventions. We investigate the UPR in glioma in the SUPR-G consortium.

Magnetic resonance imaging (MRI) is a versatile tool that can monitor how the blood vessel system of a tumor changes over time in living animals. On the other hand, Selective Plane Illumination Microscopy (SPIM, ultramicroscopy) is able to determine the structure of single cells of a particular type. We have combined these techniques and developed an imaging platform that allows the formation of tumor blood vessels and invasion of tumor cells to be precisely mapped in the setting of a preclinical study (Breckwoldt and Bode et al., 2015).

FUTURE OUTLOOK
Currently, new inhibitors are being developed, offering the possibility of combined treatments that may be more effective than using a single drug on its own. Our imaging platform will allow the therapeutic effects obtained by these new treatments to be analyzed in detail during further preclinical studies.

Contact

Dr. Björn Tews
Molecular Mechanisms of Tumor Cell Invasion (V077)

CHS Research Group at CellNetworks Heidelberg University and DKFZ
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 581
69120 Heidelberg

Tel: +49 6221 42 1570
E-Mail: b.tews@dkfz.de

Selected Publications

  • Breckwoldt M.O.*, Bode J.*, Kurz F.T., Hoffmann A., Ochs K., Ott M., Deumelandt K., Krüwel T., Schwarz D., Fischer M., Helluy X., Milford D., Kirschbaum K., Solecki G., Chiblak S., Abdollahi A., Winkler F., Wick W., Platten M., Heiland S., Bendszus M.* and Tews B.* Correlated magnetic resonance imaging and ultramicroscopy (MR-UM) is a tool kit to assess the dynamics of glioma angiogenesis. eLife 2016;5:e11712
  • Kempf A.*, Tews B.*, Arzt ME., Weinmann O., Obermair FJ., Pernet V., Zagrebelsky M., Delekate A., Iobbi C., Zemmar A., Ristic Z., Gullo M., Spies P., Dodd D., Gygax D., Korte M., Schwab ME. (2014). The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity. PLoS Biology. Recommended by F1000.
  • Tews B. et al. (2013). Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function. Proc Natl Acad Sci U S A, 110, 6583–6588.
  • Dittmann LM, Danner A, Gronych J, Wolter M, Stühler K, Grzendowski M, Becker N, Bageritz J, Goidts V, Toedt G, Felsberg J, Sabel MC, Barbus S, Reifenberger G, Lichter P, Tews B. (2011). Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro. Oncogene. 2011 Dec 12. doi: 10.1038/onc.2011.513.
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