Aim of the lab
Glioblastoma is the most aggressive brain tumor with a poor prognosis 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, as the diffusely infiltrating tumor cells, which evade surgical resection and survive treatment, inevitably give rise to reoccurring tumors.
Substantial evidence has been accumulated to suggest that lysophospholipids are involved in tumorigenesis and progression; they are especially important for therapeutic resistance of tumors by regulating tumor cell invasion. We investigate lysophospholipid signaling depending on the extracellular matrix environment in vitro and in vivo. Analyzing tumor cell-specific signaling of respective G-protein coupled receptors (GPCRs) regulating cell division, migration and invasion therefore constitutes an important part of our research. In addition, we are also interested in the impact of oxidative- and endoplasmic reticulum (ER) stress on glioma cell invasion. We are currently investigating the role of Peroxiredoxin (PRDX) function on cell invasion and survival under state of the art radio-/chemotherapies.
Our methodological repertoire includes techniques to assess GPCR activation and signaling, different in vitro paradigms to study cell migration and invasion such as organotypic slice cultures, real-time cell analyses (RTCA), time-lapse microscopy and in vivo glioma mouse models (RCAS/TVA, xenografts) for different in vivo and ex vivo whole mouse and rat brain imaging techniques we develop in our lab. Understanding these complex signaling cascades under different treatments will provide important information to design new tailored therapies for patients suffering from glioma.
1. Functional characterization of secreted proteins mediating glioma cell invasion
The invasion of the surrounding healthy brain tissues by glioma tumors does not happen randomly. It has been found to be associated with distinct anatomic structures such as the basement membranes of blood vessels as well as the subependyma. With regards to migration and invasion, the inhibitory myelin pathways also serve as essential structures for glioma in non-glioma cells (neurons, fibroblasts, other tumor cells as well as CNS metastases). The currently used standard therapies, such as radio and alkylating chemotherapy, target dividing cells. However, the invading cells do not divide, since the responsible components of the cytoskeleton direct mobility and cell division mechanisms, but not both at the same time (“go or grow” hypothesis). These cells are therefore therapy-resistant, which creates a major problem for treatment. New therapeutic agents can help stop the invasion and make the cells more susceptible to established therapeutic methods. In this connection, the Unfolded Protein Response (UPR) shows great potential as a goal for therapeutic interventions. We investigate the UPR in glioma in the SUPR-G consortium:
2. Imaging of optically cleared adult rodent brains to assess glioma-stroma interactions
We develop special glioma animal models that allow for imaging of single tumor cells and their microenvironment using light sheet microscopy (Ultramicroscopy, UM). UMThe magnified image shows the tumor-stroma border and adjacent cortex (green box) from a mouse 2 weeks after glioma implantation.
Breckwoldt M.O.* and Bode J.* et al., 2015, eLIFE
SPIM microscopy Heidelberg, SPIM microscopy, Selective Plane Illumination Microscopy, Heidelberg, ultramicroscopy, light sheet microscopy, Bjoern Tews, Björn Tews, Tews Lab, Heidelberg, Germany, Deutschland, cell migration, glioblastoma, glioma, glioma invasion, GPCR, invasion, lysophospholipids, microglia, myelin inhibitory proteins, neurons, Nogo-A, pathogenesis, PRDX1, S1P, S1PR2 signaling, sphingolipid-receptor signaling, SPIM, tumor