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Growth and differentiation factor (GDF)-15, microRNA and the immunophenotype of glioblastoma

English title Growth and differentiation factor (GDF)-15, microRNA and the immunophenotype of glioblastoma
Applicant Roth Patrick
Number 132847
Funding scheme Project funding (Div. I-III)
Research institution Neurologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.02.2011 - 31.01.2014
Approved amount 250'000.00
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Keywords (7)

glioma; GDF-15; TGF-beta; immune escape; microRNA; glioblastoma; GDF-15 and microRNA

Lay Summary (English)

Lead
Lay summary
Glioblastoma, the most common intrinsic brain tumor, has a very poor prognosis. It can occur in all age groups and affects 3 of 100,000 individuals per year. Despite several therapeutic improvements, median survival is still within the range of one year. The biological characteristics of glioma cells comprise their resistance to apoptotic stimuli, their infiltrating growth pattern which precludes a complete surgical removal and their immunosuppressive phenotype. The present project aims at characterizing a link between the cytokine GDF-15 and the microRNA repertoire of glioma cells. These experiments include stem-like glioma cells that possess stem cell properties and may contribute to the resistance of gliomas to current therapeutic approaches including immunotherapy. We will characterize mechanisms involving GDF-15 and microRNA that allow for an escape of glioma cells from an attack of the immune system. Several in vitro and in vivo models will be used and different therapeutic approaches will be applied in order to enhance the immunogenicity of glioma cells. In summary, the experiments described in this research proposal shall allow for a better understanding of glioma immunobiology and shall help to lay a scientific base for future immunotherapeutic approaches in glioblastoma patients.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Control of glioma cell migration and invasiveness by GDF-15
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, 7732-7746.
MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape
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.

Collaboration

Group / person Country
Types of collaboration
Universität Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Universität Düsseldorf Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
11th Charles Rodolphe Brupbacher Symposium: Breakthroughs in Cancer Research and Therapy Poster microRNA-mediated down-regulation of NKG2D ligand expression reduces glioma cell immunogenicity 30.01.2013 Zurich, Switzerland Roth Patrick; Codo Paula; Weller Michael;
EMBO Workshop: The reciprocal interactions of signaling pathways and non-coding RNA Poster microRNAs and the immunophenotype of malignant glioma 16.09.2012 Ascona, Switzerland Codo Paula;


Associated projects

Number Title Start Funding scheme
146213 Interferon-ß-basierte Strategien zur Ueberwindung der Therapieresistenz des Glioblastoms unter besonderer Berücksichtigung von Tumorstammzellen 01.07.2013 Project funding (Div. I-III)
170027 Defining novel targets for chimeric antigen receptor (CAR)-based immunotherapy against glioblastoma 01.07.2017 Project funding (Div. I-III)

Abstract

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.
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