MODL-30. DISSECTING THE ROLE OF MULTI-CILIOGENESIS NETWORK IN CHOROID PLEXUS TUMOR

Abstract

The choroid plexus (CP) in brain ventricles consists of a fibro-vascular core encapsulated by epithelial cells that possess clusters of primary cilia on cell surface. CP tumors are rare primary brain neoplasms that most commonly occur in young children. Compared to the benign CP papilloma, choroid plexus carcinoma (CPC) is poorly understood and highly lethal with few treatments available. Molecular, cytogenetics and genomics studies uncovered complex alterations in CPC including frequent chromosomal loss and recurrent focal aberrations, whereas abnormal NOTCH signaling is observed in many CP tumors. We showed that activation of both NOTCH and Sonic Hedgehog (SHH) signaling in mice drives the formation of aggressive CP tumor. Molecular and histology analyses demonstrated that these murine CP tumors closely resemble their human counterparts, which also display aberrant SHH and NOTCH signaling, suggesting they may represent potential therapeutic avenues. Indeed, treatment with vismodegib, an FDA-approved SHH pathway inhibitor, suppresses CP tumor growth. Unlike multi-ciliated CP epithelial cells, tumor cells in these animal models are characterized by a solitary primary cilium. Though key genes of the multi-ciliogenesis circuit driven by Geminin coiled-coil domain-containing protein 1 (GEMC1) are expressed in CP epithelium, GEMC1-dependent transcriptional program is suppressed in NOTCH-driven CP tumors. Importantly, CPCs in humans consist of tumor cells with a solitary primary cilium and exhibit profound defects multi-ciliogenesis program. Together, these results indicate that a solitary primary cilium is crucial for CPC development, whereas multi-ciliogenesis circuit possesses tumor suppressive functions and may represent a novel therapeutic target in CPC.