Mentor Name: David Gutmann

Children with the Neurofibromatosis type 1 (NF1) pediatric cancer predisposition syndrome are at increased risk of developing brain tumors, particularly low-grade gliomas of the optic nerve. These optic pathway gliomas (OPGs) cause impaired vision in 30-50% of affected children, resulting in life-long visual impairments. Leveraging Nf1-OPG genetically engineered mice, Dr. Gutmann’s team has shown that nerve cells originating in the eye (retinal ganglion cells; RGCs) control tumor growth through activation of immune system cells (T cells and microglia). These T cells and microglia produce soluble factors that create a supportive environment for tumor formation and maintenance. In addition to providing targets for therapeutic intervention, the immune system cells also serve as convergence points for systemic disease or environmental exposure. Previous studies have revealed that children with asthma, a T-cell-mediated disorder, exhibit a reduced incidence of brain tumors, including optic gliomas. This protective effect is attributed to asthma-induced T cell production of decorin, which inhibits microglia-mediated tumor support by blocking signaling, thereby suppressing glioma formation. Conversely, brain injury has been shown to exacerbate tumor progression by creating a permissive microenvironment for glioma formation. Specifically, damaged neurons stimulate glial cells IL-1ß, which in turn support glioma development. This suggests that brain injury can worsen tumor outcomes by enhancing inflammatory and growth-promoting signals involved in the tumor microenvironment. One of the other potential modifiers is gut microbiota, which has been shown to regulate traumatic brain injury and neurodegenerative disease progression. Recent studies in the Gutmann laboratory demonstrate that raising Nf1-OPG mice in a germ-free (GF) environment or treating them with specific antibiotics reduce tumor growth by suppressing CD8+ T cell infiltration. We will use 16S rRNA sequencing and metagenomic analysis to identify the specific bacterial species within the Bacteroides genus responsible for positively controlling optic glioma growth. Based on these findings, we will explore the therapeutic potential of targeting these bacteria through bacteriophage therapy, testing whether phage-mediated elimination of tumor-promoting bacteria can replicate the tumor-suppressive effects observed previously. These studies will provide critical insights into the gut-brain axis in glioma biology and set the stage for future clinical translation of microbiota-directed therapies for children with low-grade gliomas.