ORCID
https://orcid.org/0000-0002-8139-312X
Date of Award
11-5-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
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 chemotherapy with Temozolomide (TMZ) 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 in vitro. 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 TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. Further, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. Lastly, we tested whether changes in daily locomotor activity could predict GBM progression. We found that GBM cells and xenografts were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription, and that inhibiting MGMT activity abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression (Chapters 2 and 3). Further, GBM cells transduced with luciferase reporters to record clock gene expression showed intrinsic circadian rhythms in vitro and in vivo, with Bmal1 peaking at CT4 (morning) and Per2 peaking at CT18 (evening) in murine and human cell lines. Intrinsic circadian rhythms in clock gene expression in GBM entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status, and these daily glucocorticoids 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 (Chapter 4). Lastly, we found a significant decline in circadian amplitude and total activity counts in tumor-bearing mice, starting as early as one week after GBM implant (Chapter 5). Our results suggest that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity. 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 diagnosis and individual GBM patient outcomes.
Language
English (en)
Chair and Committee
Erik Herzog
Committee Members
Humsa Venkatesh; Joshua Rubin; Paul Taghert; Yao Chen
Recommended Citation
Gonzalez, Maria Felicita, "Clock Hijackers: how Integration of Glioblastoma into Circadian Circuits Regulates Tumor Progression and Sensitivity to Current Therapies" (2024). Arts & Sciences Electronic Theses and Dissertations. 3358.
https://openscholarship.wustl.edu/art_sci_etds/3358