Abstract
Glioblastoma (GBM) is the most common primary brain tumor in adults with a poor prognosis despite aggressive therapy. A recent, retrospective clinical study found that administering Temozolomide in the morning increased patient overall survival by 6 months compared to evening. Previous work has shown that murine and human models of GBM have cell-intrinsic circadian rhythms in expression of the core clock genes Bmal1 and Per2. This suggests that GBM has circadian rhythms that entrain to the hosts’ central clock. Understanding the mechanisms underlying circadian entrainment and tumor growth in GBM is essential to determine whether regulation of tumor biology and susceptibility to therapies varies with time of day. Here, we tested the hypothesis that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We found that GBM cells transduced with luciferase reporters to record clock gene expression have intrinsic circadian rhythms, with Bmal1 peaking 8-12 h before Per2 in murine and human cell lines in vitro and in vivo. Further, intrinsic circadian rhythms in clock gene expression in GBM entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We found daily glucocorticoids (i.e., Dexamethasone) promoted or suppressed GBM growth depending on time of day of administration and on the clock gene, Bmal1. Blocking circadian signals, like VIP or glucocorticoids, dramatically slowed GBM growth and disease progression. Our results suggest that GBM tumors entrain to the circadian circuit of the brain and depend on clock-controlled cues like VIP and glucocorticoids to grow at specific times of day. This work may inform personalized circadian medicine to improve individual GBM patient outcomes.