Radiation-induced proneural-mesenchymal transition in glioblastoma: how does it work and how can it be prevented?

Promoter

• De Smet Frederik, (Katholieke Universiteit Leuven (KU Leuven)), frederik.desmet@kuleuven.be

SCK•CEN Mentor

• Quintens Roel, rquinten@sckcen.be, +32 (0)14 33 28 37

SCK•CEN Co-mentor

• Tabury Kevin , ktabury@sckcen.be , +32 (0)14 33 28 16

Short project description

Gliomas are malignant brain tumors, that are believed to derive from neuroglial stem or progenitor cells. They exist in different grades defined by the World Health Organization, dependent on their degree of malignancy. The most aggressive glioma type is grade IV, generally referred to as glioblastoma (GBM). Although it is a rare disease (less than 10 cases per 100,000 adults globally per year), it is the most common primary brain tumor in adults. Since 2005, the standard treatment for GBM consists of maximal surgical resection, radiotherapy with concomitant temozolomide, followed by adjuvant temozolomide. Unfortunately, this treatment is not curative and results in a median 5-year survival of only 15 months because cancers recur due to the presence of chemo/radioresistant cancer stem cells. This highlights the importance of identifying novel methods to improve treatment, preferentially based on the specific characteristics of the tumor on an individual basis.

Resistance of tumors to radiation can be leveraged at multiple levels. At the genetic level, intrinsic radioresistance can be influenced by mutations in important oncogenes like TP53 or EGFR. However, recent advances in molecular profiling of gene expression signatures have identified molecular subtypes of GBM tumor cells with varying degrees of radiation sensitvities. Two very prevalent subtypes are classified as proneural and mesenchymal. Although tumors may be characterized by an abundance of cells from one particular subtype, most cases display heterogeneity which adds to the therapeutic challenges to target GBM, because different cellular subtypes present variable degrees of treatment sensitivity. For instance, proneural cells and tumors are in general more sensitive compared to mesenchymal ones. Unfortunately, an additional complication is the plasticity of cells. Both radiation and chemotherapeutics can drive proneural cells to become mesenchymal in a process termed proneural-to-mesenchymal transition (PMT), which is associated with tumor recurrence and therapy resistance. Deciphering the molecular mechanisms underpinning PMT is therefore of pivotal importance to understand both GBM natural evolution as well as acquired resistance to therapy.

In this project we aim to address some of these issues by identifying the molecular mechanisms that underlie radiation-induced PMT. Next, we will investigate whether we can block these to prevent the occurrence of mesenchymal differentiation both in vitro and in vivo with the ultimate aim to enhance the tumor’s sensitivity to radiation and to provide possible new avenues for better treatment strategies.

The minimum diploma level of the candidate needs to be

• Master of Sciences
• MD

The candidate needs to have a background in

• Bio-engineering
• Biology
• Medical
• Bioinformatics

Estimated duration

4 years Before applying, please consult the guidelines for application for PhD.