Meningeal-tumor interactions define distinct modes of leptomeningeal colonization in Group 3 medulloblastoma.

Medulloblastoma, the most common malignant brain tumor in children, shows a pronounced tendency to spread to the leptomeninges. Leptomeningeal metastasis accounts for nearly all medulloblastoma-related deaths, yet the cellular and molecular mechanisms driving this process remain poorly understood. Progress has been hindered by limited access to patient samples, the fragile anatomy of the leptomeninges, and the lack of robust preclinical models. Here, we developed an in vitro model that captures key features of the early leptomeningeal niche. We demonstrate that human meningeal cells promote medulloblastoma survival and proliferation under nutrient-deprived conditions both in vitro and in vivo. Using this system, we uncovered mechanisms that govern distinct patterns of leptomeningeal colonization in vivo. This physiologically informed and experimentally validated model offers a tractable platform for elucidating the molecular basis of leptomeningeal colonization and for identifying therapeutic vulnerabilities that can prevent medulloblastoma dissemination.