Language
English
Publication Date
5-1-2025
Journal
Nature Cell Biology
DOI
10.1038/s41556-025-01660-7
PMID
40263572
PMCID
PMC12081294
PubMedCentral® Posted Date
4-22-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Leptomeningeal metastases are the major source of morbidity and mortality for patients with medulloblastoma. The biology of the leptomeningeal metastases and the local tumour microenvironment are poorly characterized. Here we show that metastasis-associated meningeal fibroblasts (MB-MAFs) are transcriptionally distinct and signal extensively to tumour cells and the tumour microenvironment. Metastatic cells secrete platelet-derived growth factor (PDGF) ligands into the local microenvironment to chemotactically recruit meningeal fibroblasts. Meningeal fibroblasts are reprogrammed to become MB-MAFs, expressing distinct transcriptomes and secretomes, including bone morphogenetic proteins. Active bone morphogenetic protein signalling and co-implantation of tumour cells with MB-MAFs enhances the colonization of the leptomeninges by medulloblastoma cells and promotes the growth of established metastases. Furthermore, treatment of patient-derived xenograft mice with a PDGF-receptor-α neutralizing antibody enhances overall survival in vivo. Collectively, our results define a targetable intercellular communication cascade in the metastatic niche to treat leptomeningeal disease.
Keywords
Tumor Microenvironment, Animals, Medulloblastoma, Humans, Meningeal Neoplasms, Cerebellar Neoplasms, Meninges, Mice, Signal Transduction, Cancer-Associated Fibroblasts, Cell Line, Tumor, Platelet-Derived Growth Factor, Cell Proliferation, Receptor, Platelet-Derived Growth Factor alpha, Female, Mice, SCID, Gene Expression Regulation, Neoplastic, Transcriptomics, Cancer microenvironment
Published Open-Access
yes
Recommended Citation
Abeysundara, Namal; Rasnitsyn, Alexandra; Fong, Vernon; et al., "Metastatic Medulloblastoma Remodels the Local Leptomeningeal Microenvironment to Promote Further Metastatic Colonization and Growth" (2025). Faculty and Staff Publications. 5394.
https://digitalcommons.library.tmc.edu/baylor_docs/5394