Characterization of novel pathways that trigger resistance in glioblastoma : the role of Caspase-8

Glioblastoma multiforme (GBM) is by far the most lethal of brain tumours, with a recurrence rate of over 95% and a dismal prognosis of 12-15 months. Over the last twenty years, little to no progress has been made on the therapeutic side, with surgery and DNA damaging agents still being the only available treatment option for patients. Clinical trials have failed largely due to the huge heterogeneity of this tumour which increases the difficulty of accurate patient stratification. Moreover, GBM has a conspicuous presence of cancer stem-cells, an extensive infiltrative capacity and overactive DNA repair pathways: all characteristics that contribute greatly to tumour expansion and therapy resistance. Caspase-8 is a cysteine protease that plays a central role in the initiation and execution of apoptosis. Unexpectedly, the expression of Caspase-8 is often upregulated in GBM compared to normal tissue, suggesting the occurrence of molecular mechanisms that allow cancer cells to rewire Caspase-8 function and survive its high levels of expression. In the first part of this thesis, we investigate the role of Caspase-8 in the modulation of the inflammatory microenvironment of the tumour, which helps neo-vascularization and supports tumour infiltration in the brain parenchyma. Here we identify a novel interplay between Src kinase, constitutively activated in GBM, and Caspase8, according to which, Src-mediated phosphorylation on Caspase-8 tyrosine 380, fosters NFkB signalling and supports neo-angiogenesis. In the second part, we uncover a role of Caspase-8 as promoter of the overactive DNA repair capacity and a mediator of therapy resistance. Overall, we demonstrate that in GBM cells Caspase-8, through non-canonical functions, has a role in modulating both the inflammatory microenvironment and DNA repair. We suggest that the expression and the phosphorylation of Caspase-8 may represent novel biomarkers for GBM patients and that their targeting may be exploited to ameliorate the therapeutic response.