Elucidating the role of DNA damage and human cytomegalovirus in medulloblastoma and glioblastoma

The most common primary malignant brain tumor in children is Medulloblastoma, while Glioblastoma is the most common in adults. Treatment for both include some combination of surgery, radiation therapy, and chemotherapy. The evolution of most primary malignant brain tumors is unknown, although varying degree of genomic instability caused by defects in the DNA Damage Response (DDR) is suspected. Lately, even human cytomegalovirus (HCMV) has emerged as a suspected pathogen possibly implicated in malignant tumor evolution. Nevertheless, the causes of the chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies (i.e. radiation and chemotherapy) remain largely unknown. Thus, the main aim of this PhD thesis is to investigate the role of HCMV in the context of DDR in human Medulloblastoma and Glioblastoma. In the 1st study, we turned our attention towards Glioblastoma (GBM). We examined the ability of HCMV to induce a more aggressive cancer stem cell (CSC)-like phenotype in primary GBM cell lines. HCMV infection induced a stem cell phenotype in primary GBM cell lines as determined by changes in the cellular gene expression profile and by the conferred ability of cells to grow as neurospheres in vitro, and this phenotype was prevented by treatment with the anti-viral drug ganciclovir. As CSCs are known to be resistant to chemotherapy, our results imply that HCMV may enhance the malignancy grade of the tumor, and possibly contribute to therapy resistance. In the 2nd study, we found pronounced endogenous DNA damage signaling and constitutive activation of DNA damage checkpoint kinase cascades across our medulloblastoma cohort. The bulk of the specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and ...