Identifying Molecular Targets on Human Glioblastoma - TARGETS
Coordinating Institution:
CRP Sante
Other Partner(s):
Translational Genomics Research Institute, Phoenix (USA) ,
University of Bergen (Norway)
From: 01/04/2009
To: 31/03/2012
Budget: 504,000.00€
Contact(s):
Bjerkvig Rolf
Progress Summary 2009
Glioblastoma multiforme (GBM) is the most aggressive and infiltrative brain tumour with a very poor prognosis. The tumors grow locally in the brain and are characterized by an extreme infiltrative growth within the brain. Moreover, the tumours are highly angiogenic and show evidence of necrosis.
Based on recent findings from our laboratory, our hypothesis is that during tumour growth and progression, within a heterogenous tumour cell population, there are cells that are highly adapted to a particular micro-environment (niche). Such cells can easily trigger angiogenesis and are tumorigenic in a niche that favour angiogenesis but they do not display cancer stem cell markers. Moreover we propose that these cells are hypermethylated reflecting a selective gene expression adapted to a specific nice. However, within tumours there are also hypomethylated highly infiltrative cancer cells. Such cells share several properties of normal stem cells and can as normal stem cells utilize more of their genetic machinery to migrate into and adapt to new niches. This project is aimed at isolating the infiltrative cells in human GBMs and to identify molecular targets on these cells which we have shown to display stem like properties.
Using gene expression profiling, as well as high throughput proteomics, our laboratory has identified a number of cell surface markers associated with the invasive cells. This project aims at validating these markers in clinical material (collaboration with TGen, Phoenix Arizona). We will also use MeDIP and ChIPon chip technology to determine to what extent epigenetic mechanisms regulate the behaviour of the cancer stem-like cells. We will:
1. Use state of the art animal models to isolate the highly infiltrative non-angiogenic cancer stem-like cells from the angiogenesis dependent tumour cells.
2. Determine in detail the methylation status of highly infiltrative non-angiogenic cancer stem-like cells, as well as the angiogenesis dependent tumour cells derived from them.
3. Characterize in detail the infiltrative cell phenotype using gene expression profiling, methylation arrays and proteomics technology (several of these initiatives have already been started).
4. Validate putative targets using in house human GBM tissue arrays.
5. Functionally validate the targets using gene targeting approaches as well as genetic silencing/modification strategies.
Project Website:
