Metastatic medulloblastoma remodels the local leptomeningeal microenvironment to promote further metastatic colonization and growth
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.
Authors
- Calixto‐Hope G. Lucas (ORCID: https://orcid.org/0000-0002-8347-9592)
- Marco Gallo (ORCID: https://orcid.org/0000-0002-8451-8207)
- Kevin Y. Zhang (ORCID: https://orcid.org/0000-0002-2074-6876)
- Michelle Ly (ORCID: https://orcid.org/0000-0002-6495-8598)
- Tao Jiang (ORCID: https://orcid.org/0000-0002-8529-4487)
- Randy Van Ommeren (ORCID: https://orcid.org/0000-0002-7948-7530)
- Charles G. Eberhart (ORCID: https://orcid.org/0000-0002-2910-9427)
- Jeremy N. Rich (ORCID: https://orcid.org/0000-0001-7845-5302)
- Winnie Ong (ORCID: https://orcid.org/0000-0002-7448-4090)
- Vijay Ramaswamy (ORCID: https://orcid.org/0000-0002-6557-895X)
- Esther Mak (ORCID: https://orcid.org/0000-0002-6191-6982)
- Karen Ng (ORCID: https://orcid.org/0009-0007-2217-3446)
- Bryn Livingston (ORCID: https://orcid.org/0000-0003-4947-0081)
- Jerry Fan (ORCID: https://orcid.org/0000-0002-2381-5427)
- Hyun-Kee Min (ORCID: https://orcid.org/0000-0002-9984-6086)
- Abhirami Visvanathan
- Namal Abeysundara
- Haipeng Su
- Pasqualino De Antonellis (ORCID: https://orcid.org/0000-0001-8551-9431)
- Ning Huang (ORCID: https://orcid.org/0000-0002-8874-2601)
- Faiyaz Notta (ORCID: https://orcid.org/0000-0002-5748-3985)
- Kyle Juraschka (ORCID: https://orcid.org/0000-0002-9549-9224)
- Tajana Douglas
- Maria Vladoiu (ORCID: https://orcid.org/0000-0001-8644-0581)
- Olga Sirbu (ORCID: https://orcid.org/0000-0002-0995-2513)
- Shahrzad Bahrampour (ORCID: https://orcid.org/0000-0002-2671-3645)
- Xi Huang (ORCID: https://orcid.org/0000-0002-7177-7525)
- Vernon Fong (ORCID: https://orcid.org/0000-0003-4064-8066)
- Alexander T. Bahcheli (ORCID: https://orcid.org/0000-0001-6095-0233)
- Borja Holgado (ORCID: https://orcid.org/0000-0001-8968-0775)
- Carolina Nör
- Jüri Reimand (ORCID: https://orcid.org/0000-0002-2299-2309)
- Alexandra Rasnitsyn
- Jiao Zhang (ORCID: https://orcid.org/0000-0001-8218-3688)
- Michael D. Taylor (ORCID: https://orcid.org/0000-0001-7009-3466)
- Lei Qin
- Hailong Liu (ORCID: https://orcid.org/0000-0002-4983-8555)
- Xiaochong Wu
- Craig Daniels
- Hao Wang (ORCID: https://orcid.org/0000-0001-5461-0689)
- Jonelle G. Pallotta
Institutions
- Ontario Institute for Cancer Research (CA)
- University of North Carolina at Chapel Hill (US)
- Johns Hopkins University (US)
- Baylor College of Medicine (US)
- Capital Medical University (CN)
- University of Toronto (CA)
- Johns Hopkins Medicine (US)
- Hospital for Sick Children (CA)
- Beijing Tian Tan Hospital (CN)
- Brain Tumour Research (GB)
- SickKids Foundation (CA)
- Texas Children's Hospital (US)
- Children's Cancer Center (US)
- UNC Lineberger Comprehensive Cancer Center
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1038/s41556-025-01660-7
- Citations
- 9
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 14.63
Funders
- Rally Foundation
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health
- Stand Up To Cancer