BM-25 * PRONEURAL TRANSCRIPTION FACTOR Atoh1 DRIVES LEPTOMENINGEAL METASTASIS OF THE SONIC HEDGEHOG SUBGROUP OF MEDULLOBLASTOMA

Abstract

Medulloblastoma, the most common malignant pediatric brain tumor, arises from the cerebellum and spreads throughout the cerebrospinal fluid to the leptomeninges, covering the brain and spinal cord. Leptomeningeal metastasis, a frequent finding at diagnosis and recurrence, is a significant indicator of poor prognosis. Treatment of affected children includes irradiation of the developing brain and spine, and chemotherapy, which cause debilitating neurological complications. Despite the grave consequences of leptomeningeal metastasis, little is known about the cascade of molecular and cellular events that lead to leptomeningeal metastasis. Atonal Homolog 1 (Atoh1), a proneural transcription factor, is crucial for the initiation and progression of the Sonic Hedgehog (Shh) subgroup of medulloblastoma; Atoh1 expression is also detected in metastatic lesions of this tumor subgroup. To examine the role of Atoh1 in leptomeningeal dissemination, we generated transgenic mouse strains that conditionally express Atoh1 using Cre-loxP technology. These Atoh1 transgenic strains (A1G) were further crossed with the Math1-Cre and Ptch1+/- strains, the latter exhibiting aberrant Shh signaling in the cerebellum. Though ∼25% of Ptch1+/- mice develop non-metastatic medulloblastoma in 6-24 months, all Math1-Cre/A1G/Ptch1+/- mice succumbed to medulloblastoma within 5 months. Histological analysis revealed Pax6+ tumor cells with robust expression of Ki67, while the expression of NeuN was significantly decreased or absent, indicating the Atoh1 transgene promotes MB development in Ptch1+/- mice. More importantly, we observed robust leptomeningeal metastasis in these mice: tumor cells were detected within ventricular regions and leptomeningeal spaces covering the spinal cord in all mice, and more than 50% of animals developed metastasis in brain parenchyma, indicating Atoh1 drives leptomeningeal dissemination of medulloblastoma. Similarly, orthotopically transplanted Shh-driven medullolastoma with Atoh1 overexpression exhibited enhanced migration and invasion. Together, our results demonstrate that Atoh1 plays an important role in medulloblastoma leptomeningeal metastasis and may serve as a therapeutic target in this devastating disease.