EPEN-06. CELL ECOSYSTEM AND SIGNALING PATHWAYS OF PRIMARY AND METASTATIC PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Abstract

Childhood ependymoma is a cancer of the central nervous system with a chronic relapsing pattern. In children, 90% of ependymal tumors occur intracranially where prognosis is grim. Standard care for this disease includes surgical resection followed by radiation. Despite several clinical trials, adjuvant chemotherapies have yet to extend patient survival, highlighting a need for more effective treatment options. Ependymal tumors have been stratified into nine molecular subgroups based on their DNA methylation profile. The most prevalent and aggressive pediatric subgroup is known as posterior fossa ependymoma type A (PFA) which represents approximately 60% of pediatric cases and has a 5-year progression free survival rate of 30%. Whole genome sequencing studies have revealed that PFA tumors rarely harbor recurrent mutations. To inform the potential development of new treatment options for this disease, we sought to decipher the specific mechanisms leading to the tumorigenesis, progression, and metastasis of PFA tumors. By means of single-nuclei RNA-seq and an array of computational methods, we show that the expression profile of PFA tumor cells recapitulate the developmental lineages of radial glia in neurogenic niches, and is consistent with an origin in LGR+ stem cells and a pro-inflammatory environment. In addition, our analysis reveals the abundance of a mesenchymal cell population expressing TGF-β signaling, reactive gliosis, and hypoxia-related genes in distal metastases from PFA tumors. Taken together, our results uncover the cell ecosystem of pediatric posterior fossa ependymoma and identify WNT/β-catenin and TGF-β signaling as candidate drivers of tumorigenesis for this cancer.