Ependymoma (EPN) accounts for a substantial number of childhood deaths and over 70% of children presenting with EPN will relapse and eventually die. This tumor is a heterogeneous disease, which has been classified into nine molecular subgroups.Importantly, children with the most common type of ependymoma, posterior fossa Group A (PFA1), relapse more frequently and experience more invasive, metastatic disease at relapse. Thus, there is a critical need for more effective therapies to combat high-risk PFA1 tumors. Single-cell RNA Sequencing data suggest that the epigenetic silencing of LDOC1 within a specific subpopulation of tumor cells, mesenchymal EPN cells (MEC), has a profound, direct impact on the tumor biology of PFA1 tumors. The driving hypothesis is that epigenetic silencing of LDOC1 in the MEC subpopulation, because of chromatin remodeling, is the molecular driver in PFA1 EPN, through upregulation of NF-KB signaling. To address this hypothesis, aim one will determine the role of LDOC1 expression in EPN by examining 1) the mechanism of gene silencing, 2) the functional role of loss of LDOC1 in vitro and in vivo, and 3) the genomic transcriptional targets of LDOC1. The collective proposed studies may reveal a previously uncharacterized role of LDOC1 in MEC subpopulations of PFA1 tumors, as well as will define the effect of LDOC1 loss, which we hypothesize to be the molecular driver of tumor biology of PFA1 EPN. These studies will significantly add to our understanding of childhood EPN and have the potential to identify rational therapeutic targets for children with this high-risk, poor-outcome pediatric brain tumor.
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