DS-03 * SONIC HEDGEHOG ANTAGONISTS POTENTLY INDUCE APOPTOSIS IN THE CEREBELLAR EXTERNAL GRANULE LAYER: IMPLICATIONS FOR MEDULLOBLASTOMA TREATMENT

Abstract

There is a great interest in Hedgehog signaling both for its role in cerebellar development and medulloblastoma (MB) treatment. The cerebellum maintains its own proliferative layer called the external granule layer (EGL) that produces over 90% of its neurons. During development, the established dogma views Hedgehog signaling as a robust mitogenic stimulator of EGL proliferation. However, in other regions of the body, Hedgehog stimulation acts as a survival signal by potently inducing NPC apoptosis when signaling is lost. In this manner, the sonic hedgehog ligand's concentration gradient determines NPC survival or death thereby morphologically sculpting the developing nervous system. Therefore, we tested whether Hedgehog signaling also acts as a survival signal in the EGL by administering several Hedgehog antagonists (vismodegib, cyclopamine, and jervine). Remarkably, we found all Hedgehog antagonists (HAs) potently induced EGL apoptosis within a few hours of administration. This suggests a large portion of the HAs' anti-proliferative effects are due to the apoptotic loss of a large number of EGL NPCs. This research may also have important implications for MB formation and treatment. There is convincing evidence that EGL neural progenitor cells (NPCs) can be the tumor initiating cells for MBs (the most common malignant brain tumor in children). Therefore, we examined if HAs can also produce apoptosis in Patched mice which exhibit constitutive Hedgehog stimulation and are prone to MB formation. We found HA administration also potently increased apoptosis in both EGL NPCs and preneoplasms. This may have important implications for the treatment of MBs with HAs. For example, apoptosis involves signaling mechanisms distinct from proliferation that may need to be disabled for malignant transformation. In addition, the requirement for Hedgehog signaling may prevent metastasis by killing tumor cells as they spread to regions where such signaling is absent.