Document text
Principal Investigator: Benjamin Deneen
Organization: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
Fiscal Year: 2024
Award: $591,375
Funding agency: National Cancer Institute
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.
Terms: <BRG-1><BRG-1 Gene><BRG1><BRG1 Gene><BRM/SWI2-Related Gene-1><Bar Codes><Basal Transcription Factor><Basal transcription factor genes><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Cancers><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><Childhood Malignant Brain Tumor><Chromatin><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Clinical><Collection><Coupled><Data><Development><Differential Gene Expression><Disparate><EEG><Electroencephalogram><Electroencephalography><Electroporation><Embryo><Embryonic><Encephalon><Ependymoma><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Expression Signature><Gene Action Regulation><Gene Down-Regulation><Gene Expression><Gene Expression Profile><Gene Expression Regulation><Gene Fusion><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic><Genetic Transcription><Genome><Glia><Glial Cells><Goals><Growth><Histones><Human><Hyperactivity><Knowledge><Kolliker's reticulum><Lead><Maintenance><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mediator><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NFKB3><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurons><Neuropeptide Tyrosine><Neuropeptides><Neurotransmitters><Non-neuronal cell><Nonneuronal cell><Oncogenesis><Oncogenic><Pathway interactions><Patients><Pb element><Pediatric Malignant Brain Tumor><Proteins><RELA><RELA gene><RNA Expression><Radial><Radius><Regulation><Repression><Role><SMARCA4><SMARCA4 gene><SNF2-Beta><SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 Gene><Seizures><Shapes><Site><Synapses><Synaptic><T-Stage><Testing><Tissue Growth><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription Repression><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transcriptional Repression><Tumor stage><WHO Grade II Ependymal Neoplasm><WHO Grade II Ependymal Tumor><barcode><cancer progression><childhood brain cancer><chromatin modifier><developmental><electroporative delivery><epigenetically><epigenomics><gene electrotransfer><gene expression pattern><gene expression signature><gene repression><gliogenesis><heavy metal Pb><heavy metal lead><human model><in utero><lead candidate><loss of function><malignancy><member><model of human><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><nerve cement><neuronal><neuronal tumor><neuropeptide Y><novel><ontogeny><overexpress><overexpression><pathway><pediatric brain cancer><programs><protein protein interaction><screening><screenings><social role><synapse><transcription factor><transcriptional profile><transcriptional signature><tumor><tumor initiation><tumor progression><tumorigenesis><tumors in the brain>