Juncal Aldareguia Fernández. Onkologia Zelularra Taldea, Biodonostia OII.

Idoia Garcia Dk eta Ander Matheu Dk.




Brain tumors, such as glioblastoma (GB) in adults and medulloblastoma (MB) in children, represent one of the most important challenges in current medicine, since they resist existing therapies, recur and spread. These tumors present a high heterogeneity, since they host a subpopulation of cancer stem cells (CSCs), responsible for metastasis, treatment resistance and tumor recurrence. Moreover, the deregulation of genes related to embryonic development and stem cell maintenance, such as ERBB4 and SOX1, seems to be critical for the development and progression of their malignant phenotype. The main objective of this doctoral thesis is to determine the function of both genes in GB and MB, as well as to establish their relationship with tumor-specific CSCs (GSCs and MBSCs, respectively). Firstly, we observed that ERBB4 has an essential role in cerebellum development, controlling the migration of the population of progenitor cells. Furthermore, we determined that ERBB4 is highly expressed in Group 4 MBs and SOX1 in SHH Group ones, being associated in both cases to a worse survival. By inhibiting the expression of ERBB4 and SOX1, we observed a reduction in cell viability, self-renewal capacity, and tumor initiation and progression. We also identified an enrichment of SOX1 and ERBB4 expression in MBSCs. We also established a relationship between high SOX1 expression and poor survival in GB, in addition to the enrichment of its expression in GSCs. Finally, by inhibiting the expression of SOX1 in GB, we observed a decrease in tumor proliferation, initiation and progression. Overall, our results suggest a hitherto undescribed oncogenic role of ERBB4 and SOX1 in MB and GB.

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