glioma; GDF-15; TGF-beta; immune escape; microRNA; glioblastoma; GDF-15 and microRNA
Paula Codo, Michael Weller, Kerstin Kaulich, Daniel Schraivogel, Manuela Silginer, Guido Reifenberger, Günter Meister, Patrick Roth (2016), Control of glioma cell migration and invasiveness by GDF-15, in Oncotarget
Codo Paula, Weller Michael, Meister Gunter, Szabo Emese, Steinle Alexander, Wolter Marietta, Reifenberger Guido, Roth Patrick (2014), MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape, in Oncotarget
Malignant gliomas are intrinsic tumors of the brain with a dismal prognosis despite multi-modal therapy. They are characterized by diffuse infiltration of the surrounding healthy brain tissue, well-adapted to hypoxic conditions and regarded as paradigmatic for tumor-associated immunosuppression. In this regard, transforming growth factor (TGF)-beta has been delineated as a central regulator of immune escape mechanisms including a down-regulation of ligands to the activating immune cell receptor, NKG2D. Moreover, TGF-beta has been attributed a major role in maintaining the cancer stem cell reservoir in glioblastoma. We have delineated growth and differentiation factor (GDF)-15, a member of the TGF-beta family, as a glioma-associated molecule that contributes to the malignant phenotype of gliomas, by demonstrating that GDF-15 promotes glioma cell proliferation and confers protection from immune cell attack. In the present project, we first aim at assessing the expression of candidate microRNA (miRNA) by glioma cells including glioma stem cells that regulate the expression of NKG2D ligands. miRNA are a novel class of small RNA molecules involved in the regulation of numerous cellular mechanisms. We will examine the impact of TGF-beta and other important parameters in the glioma context such as hypoxia and irradiation on the expression of these miRNA. Finally, we will use antagomirs to silence selected miRNA in glioma cells and characterize their ability to increase the susceptibility of glioma cells towards immune cells in vitro and in vivo.We will then define the role of GDF-15 for the biology of these tumors more precisely and characterize the influence of glioma-derived GDF-15 on the miRNA profile of these cells. We will identify miRNA that are expressed in a GDF-15-dependent manner in gliomas and characterize their impact on glioma cell proliferation, migration and immune escape. The identification and characterization of the network consisting of GDF-15, miRNA and NKG2D ligands shall help to define novel therapeutic strategies against these lethal tumors.