Team description

Keywords: 

Glioblastoma multiforme (GBM), the most common form of human brain cancer in adults, are associated with aberrant gene expression, an altered metabolism and dysregulation of apoptosis. As indicated by its name, glioblastoma multiforme are very heterogeneous tumors. This is likely to explain the wide array of responses to anti cancer treatments recorded.

The cascade of event leading to tumor development begins with mutations in a pool of cells and ends with the construction of a complete tumoral microenvironment that permits tumor survival and progression. Accordingly, it is important to understand along with the characteristics of tumoral cells, the role of the microenvironment in tumoral progression. Several studies have suggested that malignant glioma may derive from mutated neural stem/progenitor cells

Our view of this devastating pathology has been challenged by two new concepts: the importance of hypoxia in tumor progression and in the acquisition of the resistance treatments and the existence of cancer stem cells.

Most, if not all, cancers are characterized by ROS overproduction. However, the mechanisms of ROS signaling in the survival and death of cancer cells have not clearly been established. It has been suggested that moderate oxidative stress can stimulate proliferation and survival of cancer cells while a sudden enhancement in ROS results in apoptosis and cell death. We have shown that modulation of oxidant stress can have a direct impact in tumor growth in rats in vivo.

Glioma stem cells have been shown to reside preferentially in specific niches, the characteristics of which are known to influence cellular responses to treatments especially radiation; treatments and especially radiation modifies environmental factors. Thus, depending of the environmental conditions and of the treatments the induction of ROS will produce opposite effects. However the control, regulation, outcome and production of ROS in CSC, outside and inside the niche, have not been extensively studied and might represent an important therapeutic target. Recent data have established that transient elevation of ROS levels control self-renewal and neurogenesis of neural stem/progenitor cells.

The work of our team, in the past 10 years, has been focussed on apoptosis and more specifically on the basic mechanisms of action of the Bcl-2 family in human and murine gliomas. Our group has developed an expertise on the studies of mitochondria-related apoptosis in central nervous system cancers with a special emphasis on cancer stem cells. It has contributed to this field by publishing more than 100 papers . The team has developed the cellular and molecular biology tools to study mitochondrial apoptosis in cancer and normal stem cells.

Conclusion: the aim of this project is to characterize the hypoxia signaling pathway in cancer stem cells and to understand its importance in the maintenance and the survival of Brain Tumor Stem Cells (BTSC) via the inhibition of apoptosis. Along with this analysis, we will also investigated the effects of drugs or compounds that affect hypoxia or glycolytic metabolism on BTSCs' apoptosis as these cells have been shown to be highly resistant to death inducers. Another aspect of this project will be to examine the relationship between hypoxia and epigenetic regulations as preliminary results suggest an important connection between them.

Collaborations

Pr V. Coronas (University of Poitiers)

Pr O. Herault (University of Tours)

Pr Heymann (University of Nantes)

Institut de Recherche en Santé de l'Université de Nantes

8 quai Moncousu