Abstract A014: Primary tumor geometry and growth architecture influence leptomeningeal metastasis in medulloblastoma

Abstract

Leptomeningeal metastasis is the leading contributor to mortality in children diagnosed with medulloblastoma, the most prevalent malignant brain tumor in pediatrics. Understanding the factors that influence the development of leptomeningeal dissemination is critical for improving therapeutic strategies. However, advancements in leptomeningeal metastasis biology have been hindered by multiple barriers, one of which is the limited incidence of leptomeningeal dissemination in murine models of medulloblastoma. In children, medulloblastoma can localize to the cerebellar hemispheres or in the midline next to the 4th ventricle. Interestingly, the hemispheric tumors display significantly less metastatic capacity. This led us to hypothesize that the tumor geometry, growth architecture and anatomical location of the primary tumor may influence the development of disseminated disease in medulloblastoma models. To test this hypothesis, we implanted medulloblastoma cell lines representative of the disease subgroups using three distinct intracranial injection approaches: shallow injections (non-disruptive to the fourth ventricle), deep injections (targeting regions adjacent to the fourth ventricle recess out tracks) and paramidline injections (directly adjacent to the 4th ventricle, but not disruptive). We monitored tumor growth and dissemination to assess the relationship between tumor geometry and injection depth and the development of leptomeningeal metastasis. Shallow injections produced localized primary tumors with little evidence of leptomeningeal spread. In contrast, deep injections that disrupted the fourth ventricle led to a higher incidence of leptomeningeal metastasis, particularly along the leptomeninges of the spinal cord. These findings suggest that the primary tumor geometry in combination with growth architecture of primary tumors play a key role in leptomeningeal dissemination patterns. Furthermore, location of primary tumor development and growth patterns (circumscribed, locally or infiltrative disruptive) impact overall metastatic burden. This model provides a valuable platform for studying disseminated disease and evaluating novel therapies aimed at preventing or treating leptomeningeal metastasis in pediatric brain tumors.