MEDU-07. THE DEVELOPMENTAL STAGE OF THE MEDULLOBLASTOMA CELL-OF-ORIGIN IS MAINTAINED IN CANCER AND RESTRICTS HEDGEHOG PATHWAY USAGE AND DRUG SENSITIVITY

Abstract

Sonic Hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) population that depends on Hedgehog signaling for its expansion. While SHH tumors are characterized by an overall deregulation of this pathway, they also exhibit aberrations that are specific for patient age. To investigate if the developmental stage of the tumor cell-of-origin can account for these age-specific lesions, we compared transcriptomes from developing mouse CGNPs and observed highly dynamic gene expression changes as function of age. Cross-species comparison with a cohort of SHH medulloblastoma showed partial maintenance of these patterns in the different medulloblastoma patient-age groups. In particular, we found low primary cilia expression in early CGNPs and infant medulloblastoma, which coincided with insensitivity to Smoothened manipulation. Together, these findings can explain the absence of SMOOTHENED mutations in infant patients and suggest that drugs targeting the SHH pathway downstream of SMOOTHENED will be most appropriate for infant patients.