Glioblastoma is the most common primary malignant brain tumour in the adult population.
Despite multimodality treatment with surgery, radiotherapy and chemotherapy, outcomes are
very poor, with less than 15% of patients alive after two years. Increasing evidence suggests
that glioblastoma stem cells (GSCs) are likely to play an important role in the biology of this
disease and are involved in treatment resistance and tumour recurrence following standard
therapy.
My thesis aims to address two main aspects of this research area: 1) optimization of methods
to evaluate treatment responses of GSCs and their differentiated counterparts (non-GSCs),
with a particular focus on a tissue culture model that resembles more closely the tumoral
niche; 2) characterization of cell division and centrosome cycle of GSCs, investigating possible
differences between these cells and non-GSCs, that would allow the identification of targets
for new therapeutic strategies against glioblastomas.
In the first part of my project, I optimized a clonogenic survival assay, to compare sensitivity of
GSCs and non-GSCs to various treatments, and I developed the use of a 3-dimentional tissue
culture system, that allows analysis of features and radiation responses of these two
subpopulations in the presence of specific microenvironmental factors from the tumoral niche.
In the second part, I show that GSCs display mitotic spindle abnormalities more frequently
than non-GSCs and that they have distinctive features with regards to the centrosome cycle. I
also demonstrate that GSCs are more sensitive than non-GSCs to subtle changes in Aurora
kinase A activity, which result in a rapid increase in polyploidy and subsequently in senescence,
with a consistent reduction in clonogenic survival. Based on these findings, I propose that
kinases involved in the centrosome cycle need to be explored as a novel strategy to target
GSCs effectively and improve outcomes of glioblastoma patients
