Transcriptional Regulation in ZFTA-RELA Ependymoma

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SUMMARY Transcriptional networks in cancer are a collection of inputs from developmental and cell identity programs, oncogenic proteins, metabolic circuits, and micro-environmental interactions. Together, these culminate to drive disparate stages of tumor initiation, maintenance, and progression. Ependymoma (EPN) is an aggressive form of pediatric brain cancer driven by a single genetic event, a gene fusion between ZFTA and RELA. ZFTA-RELA (denoted ZRFUS) is a potent driver of transformation, and its expression is sufficient to induce EPN when expressed in the developing mouse brain. Despite evidence that ZRFUS functions as an aberrant transcriptional regulator, the downstream mechanisms it utilizes to drive tumorigenesis remain poorly defined. This knowledge gap has hindered the identification of clinically tractable approaches for EPN, which have remained stagnant for over 30 years. Therefore the overarching goal of this proposal is to dissect how ZRFUS impacts and intersects with the diverse transcriptional programs that drive EPN tumorigenesis. To dissect how ZRFUS drives EPN tumorigenesis, we established the first autochthonous mouse model of ZRFUS EPN using in utero electroporation (IUE) of the developing mouse brain. Using this model, we demonstrated that transcription factor (TFs) essential for developmental gliogenesis, such as SOX9, are required for the initiation of ZRFUS EPN development. Barcode screening of these developmental TFs in our model identified ETV5 as a lead candidate that is both necessary and sufficient for ZRFUS progression. Further examination of ETV5 function in EPN revealed that it suppresses gene expression by promoting repressive chromatin states. Among the key target genes repressed by ETV5 is Neuropeptide Y (NPY), a potent neurotransmitter, which we found functions to suppress ZRFUS progression and remodel neuronal synapses in the peritumoral margins towards decreased activity. Based on these compelling preliminary studies, we hypothesize that developmentally encoded TFs govern tumor initiation and manipulate chromatin accessibility that regulate tumor-neuron interactions in the brain microenvironment to drive EPN growth. This hypothesis will be tested in the following aims: 1) Determine how SOX9 impacts ZRFUS EPN initiation through modifying chromatin accessibility, 2) Decipher the role of ETV5 in ZRFUS EPN progression, and 3) Define the role of NPY in remodeling the ependymoma neuronal microenvironment.