Glioblastoma (GBM) is an aggressive central nervous system neoplasia with an extremely poor prognosis. Despite intense research, 5-year survival rates have not increased for the past 20 years, pointing to the need for alternative therapeutic strategies. Accumulating evidence has described a role for cytomegalovirus (CMV) in GBM, yet the mechanism of action is still unclear. We hypothesized that CMV may be metabolically reprogramming GBM cells and that these changes may alter the tumor microenvironment (TME) resulting in enhanced tumor progression. To test this hypothesis we infected GBM cells with CMV and employed the Seahorse Bioanalyzer and flow cytometry to examine their metabolic function. We witnessed increased glycolysis and oxidative phosphorylation relative to control cells. These changes were also accompanied by increases in lactate and reactive oxygen species (ROS) production. Since both lactate and ROS are capable of producing significant tumor promoting effects within the TME, we examined the impact that CMV-infected cells had on their neighbors by employing an indirect co-culture model. We found that, independent of viral transmission, the secretome of infected GBM cells was able to alter the levels of key metabolic proteins and epigenetic marks of their neighbors. These findings suggest the potential for major alterations within the TME following CMV infection or reactivation. They point to an oncomodulatory role for CMV in the context of GBM and may underlie the enhanced disease progression seen in CMV positive patients. Further research into these findings may yield new therapeutic targets which could be exploited to treat GBM more effectively.
National Institute of General Medical Sciences of the National Institute of Health P20GM103629 pilot grant (to K.J.Z), Tulane University Faculty Research Enhancement Funds (to K.J.Z), and Louisiana Board of Regents predoctoral fellowship LEQSF (2017-22)-GF-11 to (M.A.A.H).
