Aberrant Signaling from Brain Tumors Regulates Distant and Local Environments

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ABSTRACT Perturbations in redox signaling are associated with multiple neurological disorders, ranging from neurodegenerative diseases to brain tumors. The brain tumor glioblastoma (GBM) is a devastating disease and improved understanding of its altered bioenergetics and redox status is likely to improve treatment options. GBM is highly heterogeneous and includes cells that have altered redox states and similarities to neural stem cells, called brain tumor initiating cells (BTICs), that cause tumor recurrence. A redox regulator we identified as being elevated in BTICs is GTP cyclohydrolase I (GCH1), a gene known to be altered in dopa-responsive dystonia and Parkinson’s disease. Importantly, GCH1, a rate-limiting enzyme that produces tetrahydrobiopterin (BH4), maintains BTIC survival via suppressing damage caused by reactive oxygen species (ROS). Mitigating ROS via GCH1 is one mechanism by which BTICs may survive hostile tumor microenvironments, like nutrient deprivation. As redox biology and metabolism are closely linked, I hypothesize that the metabolic consequence of high GCH1 confers protection to oxidatively vulnerable lipids to support BTIC growth. My current findings during the F99 phase strongly suggest that the GCH1/BH4 pathway increases lipid utilization and plays a vital role in protecting oxidatively vulnerable lipids during metabolic reprogramming. The successful investigation of oxidative stress responses via GCH1 and its relationship with metabolism will reveal metabolic vulnerabilities for clinical intervention. In addition, my studies are likely to be informative for other neurodegenerative diseases where GCH1 is altered, or ROS is unregulated. For the K99 phase, continued studies in brain tumor models will shift focus toward elucidating the impact of GBM on the bone marrow (BM) microenvironment in regulating immune suppression and myeloid recruitment. Infiltrating BM cells are a significant contributor to the tumor microenvironment where GBM co-opts these cells to drive disease progression. Brain tumors are excitatory cells that readily release/uptake neurotransmitters for their growth, but this high neural activity has not been investigated in the BM, despite the BM being innervated. BM cells have several neuroreceptors, suggesting these cells can readily respond to neural cues. As BM innervation is important for its maintenance and immune mobilization, aberrant neural activity from GBM that remodel the BM is unexplored. Therefore, using BM denervation studies in GBM models, I will assess neural activity as a critical player in myeloid skewing in the BM and recruit immunosuppressive myeloid cells to the brain. Elucidating the crosstalk between glioma-to-bone marrow through neural communication provides an opportunity to disrupt signaling pharmacologically without having to consider drugs for blood brain barrier penetrance.