Poster abstracts
Poster number 59 submitted by Leyre Jimenez Garcia
Differential tumor:meningeal interactions drive leptomeningeal colonization patterns in medulloblastoma metastasis
Leyre Jimenez Garcia, MS (Molecular, Cellular, and Developmental Biology Graduate Program), Lindsay N. Ryan, BS (Nationwide Childrens Hospital), Amy C. Gross, MS (Nationwide Childrens Hospital), Annika M. Albrecht, Jefferson H. Walters, Ryan D. Roberts, MD, PhD (Nationwide Childrens Hospital, The James - CCC at The Ohio State University), James B. Reinecke, MD, PhD (Nationwide Childrens Hospital, The James - CCC at The Ohio State University)
Abstract:
Leptomeningeal metastasis remains the predominant cause of death for children and young adults with medulloblastoma, the most common malignant pediatric brain tumor. Despite significant advances in understanding the molecular and developmental origins of medulloblastoma, the mechanisms underlying leptomeningeal dissemination remain poorly characterized. This gap in knowledge represents a significant limitation in the development of novel therapeutic strategies that can improve patient outcomes. The inaccessibility of patient-derived leptomeningeal tissue and the underrepresentation of metastasis in preclinical medulloblastoma murine models represent several factors that have impeded progress in understanding leptomeningeal metastasis. To overcome these barriers, we designed an in vitro platform to mimic the early in vivo leptomeningeal niche by culturing human primary leptomeningeal fibroblasts with medulloblastoma cells under serum- and growth factor-free conditions. Using this method, we have successfully cultured eight established and patient-derived medulloblastoma cell lines. In children, medulloblastoma displays two distinct but poorly characterized leptomeningeal growth patterns: laminar, characterized by extensive diffuse spreading throughout the leptomeninges, or nodular, marked by discrete tumor masses. Our co-culture model reproduces this heterogeneity in growth patterns, and for the first time, identifies and validates preclinical medulloblastoma models that display both laminar and nodular morphologies. Furthermore, time-lapse imaging of the co-culture revealed that laminar cells disrupt the leptomeningeal layer and spread along the underlying basement membrane, while nodular lesions remain anchored to an intact meningeal surface. Collectively, based on results obtained in vitro and validated in vivo, we propose a new model for leptomeningeal colonization in medulloblastoma. We are now using this in vitro platform to conduct cellular and molecular assays that identify and test novel agents effective in disrupting leptomeningeal colonization.
Keywords: Medulloblastoma, Metastasis, TumorHost interactions