Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host
Maria F. Gonzalez-Aponte, Anna R. Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B. Rubin, Erik D. Herzog
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry . Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids. • Glucocorticoids promote glioblastoma (GBM) growth in a time-of-day dependent manner • Loss of daily glucocorticoid signaling reduces GBM growth and disease progression • Mouse and human GBM cells have intrinsic daily rhythms that synchronize to the host • Glucocorticoids synchronize daily clock gene expression in GBM Gonzalez-Aponte et al. identify daily glucocorticoid receptor signaling as an intrinsic driver of glioblastoma (GBM) progression and a synchronizer of tumor clock gene expression to the host. This work provides an intrinsic circadian driver, and therapeutic target, to slow GBM growth, and offers considerations for glucocorticoid use in the clinic.