Notch-mediated suppression of multiciliate differentiation promotes choroid plexus tumor initiation from progenitors in response to epithelium-derived Sonic Hedgehog

Aberrant Notch signaling has been linked to many cancers including choroid plexus (CP) tumors, a group of rare and predominantly pediatric brain neoplasms. We developed animal models of CP tumors by inducing sustained expression of Notch1 that recapitulate properties of human CP tumors with aberrant NOTCH signaling. Whole transcriptome and functional analyses showed that tumor cell proliferation is associated with Sonic Hedgehog (Shh) in the tumor microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumor cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate diffferentiation. A Shh-driven signaling cascade in the primary cilium occurs in tumor cells but not in epithelial cells. Lineage studies show that CP tumors arise from mono-ciliated progenitors in the roof plate characterized by elevated Notch signaling. Abnormal SHH signaling and distinct ciliogenesis are detected in human CP tumors, suggesting SHH pathway and cilia differentiation as potential therapeutic avenues. Gene expression profiling was performed on CP tumors in Math1-cre;Rosa26-NICD1 animals and wild type CPs at day P0 and day P21 using a microarray approach. Three sets of tumor specimens from Math1-cre;Rosa26-NICD1 mice and three sets CP specimens from wild type mice were collected at each time point. To ensure that sufficient amount of RNA can be extracted, each set of specimens included tissues pooled from several animals of the same genotype.