EZH2-Myc driven glioblastoma elicited by cytomegalovirus infection of human astrocytes

Mounting evidence is identifying human cytomegalovirus (HCMV) as a potential oncogenic virus. HCMV has been detected in malignant gliomas. EZH2 and Myc play a potential oncogenic role, correlating with the glioma grade. Herewith, we present the first experimental evidence for HCMV as a reprogramming vector, straight through the dedifferentiation of mature human astrocytes, and generation of CMV-Elicited Glioblastoma Cells (CEGBCs) possessing glioblastoma-like traits. HCMV counterparts the progression of the perceived cellular and molecular mechanisms succeeding the transformation and invasion processes with CEGBCs involved in spheroid formation and invasiveness. Glioblastoma multiforme (GBM) biopsies were characterized by an elevated EZH2 and Myc expression, possessing a strong positive correlation between the aforementioned markers in the presence of HCMV. From GBM tissues, we isolated HCMV clinical strains that transformed HAs toward CEGBCs exhibiting upregulated EZH2 and Myc. Spheroids generated from CEGBCs possessed invasion potential and were sensitive to EZH2 inhibitor, ganciclovir, and temozolomide triple therapy. HCMV clinical strains transform HAs and fit with an HCMV-induced glioblastoma model of oncogenesis, and supports the tumorigenic properties of Myc and EZH2 which might be highly pertinent in the pathophysiology of astrocytic brain tumors and thereby paving the way for new therapeutic strategies.

Automated summary

Mounting evidence suggests that human cytomegalovirus (HCMV) may be an oncogenic virus, as it has been found in malignant gliomas. The oncogenic proteins EZH2 and Myc have been correlated with glioma grade. This study provides experimental evidence that HCMV can reprogram mature human astrocytes into CMV-Elicited Glioblastoma Cells (CEGBCs) with glioblastoma-like traits. These CEGBCs exhibit spheroid formation and invasiveness, suggesting a role for HCMV in the transformation and invasion processes. Clinical strains of HCMV isolated from glioblastoma patients transformed human astrocytes into CEGBCs with upregulated EZH2 and Myc. These findings highlight the importance of Myc and EZH2 in the pathophysiology of astrocytic brain tumors and suggest new therapeutic strategies.