Investigating the effect of GPNMB on the growth of malignant glioma

• Applicant: Dr. Frank Szulzewsky
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 288857840

Patients suffering from Glioblastoma only have a median survival of 12-15 months after diagnosis. Despite gross-total resection, radio- and chemotherapy there is currently no successful treatment for these tumors.Microglia and peripheral macrophages and monocytes accumulate in and around the glioma tissue. However, these cells become polarized by the tumor cells and support glioma growth. During my doctoral thesis I could show by gene expression analysis (microarray) that mouse glioma-associated microglia/macrophages highly express the gene GPNMB. In addition, Patient data showed that Glioblastoma patients with a lower GPNMB expression in the tumor tissue exhibited a significantly longer overall survival time.In this current project I want to explore the role and function of GPNMB in Glioblastoma and in glioma-associated microglia/macrophages and the influence of GPNMB on glioma growth.As I could previously show that GPNMB is expressed in the tumor cells per se, as well as in the tumor stroma, which means non-neoplastic glioma-associated cells (for example invading immune cells, astrocytes, pericytes), I will focus my research on both cell types.During this project I will first investigate the expression of the different GPNMB isoforms in the different cell types in Glioblastoma. In addition, I will investigate the influence of GPNMB overexpression and knockdown in the tumor cells. For this I will use the RCAS-PDGFb glioma model, which allows the de novo generation of high grade gliomas, resembling human Glioblastoma, in immune competent mice by viral gene transfer. Lastly, I will explore the role of GPNMB expression in the tumor stroma. For this I will reimplant cultured RCAS-PDGFb tumor cells into GPNMB knockout mice and compare the tumor growths and the cellular composition with wild type mice.As there are currently no effective therapies for Glioblastoma it is necessary to explore new therapeutic approaches. This might include a modulation of the tumor stroma to inhibit the tumor growth. GPNMB might pose a valuable target in glioma research. This project is therefore necessary and worthwhile to investigate the different functions of GPNMB in glioma cells and the glioma microenvironment. Elucidating the role of GPNMB might give valuable information about how the microenvironment supports glioma growth and how this interaction is mediated. This knowledge will hopefully help to shape new therapies against glioma.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Eric Holland, Ph.D.