Jaione Auzmendi Iriarte. Grupo de Oncología Celular, IIS Biodonostia.
Dr. Ander Matheu Fernández
Salón de actos del Hospital Universitario Donostia.
At first glance, cancer and aging may seem opposite processes. However, they both share the accumulation of cellular damage as a common origin and they present huge similarities in their main hallmarks, indicating that they are two distinct manifestations of the same underlying mechanisms. Among these hallmarks, the dysregulation of the stem cell pool is of special interest. In glioblastoma, the most common and aggressive primary brain tumor in adults, a small subpopulation of glioma stem cells (GSCs) has been described as responsible for tumor initiation, progression, clonal heterogeneity, therapy resistance and tumor recurrence. In this doctoral thesis, we demonstrate that chaperone-mediated autophagy promotes tumorigenic properties of GSCs by regulating proteomic and transcriptomic pathways associated with proliferation, self-renewal, mitochondrial function, immune response and interactions with the extracellular matrix. On the other hand, we reveal that histone deacetylase (HDAC)-6 expression is enriched in GSCs, and we characterize the effect of a novel HDAC6 inhibitor with high target selectivity and cytotoxic effect on GSCs, even more potent than other currently available HDAC inhibitors. In addition, we extend the study of HDACs to the context of brain aging, showing that HDAC expression is increased in aged hippocampal neurogenic niche, positively correlating with microglial aging both in vitro and in vivo.