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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.<\/jats:p>","DOI":"10.1186\/s40478-026-02253-7","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T08:06:14Z","timestamp":1775030774000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Meningeal-tumor interactions define distinct modes of leptomeningeal colonization in Group 3 medulloblastoma"],"prefix":"10.1186","volume":"14","author":[{"given":"Leyre","family":"Jimenez Garcia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay N.","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C.","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika M.","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jefferson H.","family":"Walters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Leonard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Reinecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"issue":"12","key":"2253_CR1","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/S2352-4642(20)30246-7","volume":"4","author":"RM Hill","year":"2020","unstructured":"Hill RM et al (2020) Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. 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According to institutional and national guidelines, research involving such cell lines does not require ethics committee approval because the material is anonymized and information identifying the donor is not accessible. Animal care and experiments were approved by the Institutional Animal Care and Use Committee of the Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital (IACUC protocol #AR15-00022).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"De-identified MR images were obtained after approval from Nationwide Children\u2019s Hospital Institutional Review Board. Consent was not deemed to be necessary.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"108"}}