Metastatic medulloblastoma remodels the local leptomeningeal microenvironment to promote further metastatic colonization and growth.

in Nature cell biology by Namal Abeysundara, Alexandra Rasnitsyn, Vernon Fong, Alexander Bahcheli, Randy Van Ommeren, Kyle Juraschka, Maria Vladoiu, Winnie Ong, Bryn Livingston, Pasqualino de Antonellis, Michelle Ly, Borja López Holgado, Olga Sirbu, Shahrzad Bahrampour, Hyun-Kee Min, Jerry Fan, Carolina Nor, Abhirami Visvanathan, Jiao Zhang, Hao Wang, Lei Qin, Ning Huang, Jonelle Pallotta, Tajana Douglas, Esta Mak, Haipeng Su, Karen Ng, Kevin Yang Zhang, Craig Daniels, Calixto-Hope G Lucas, Charles G Eberhart, Hailong Liu, Tao Jiang, Faiyaz Notta, Vijay Ramaswamy, Jüri Reimand, Marco Gallo, Jeremy N Rich, Xiaochong Wu, Xi Huang, Michael D Taylor

TLDR

  • Researchers investigated the biology of leptomeningeal metastases in medulloblastoma and identified a targetable intercellular communication cascade involved in tumor progression.
  • PDGF-receptor-alpha neutralizing antibodies may be a promising therapeutic strategy for treating leptomeningeal disease.

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.

Overview

  • The study focuses on leptomeningeal metastases in medulloblastoma patients, exploring the biology of the metastatic niche and its significance in tumor progression.
  • The researchers investigate the role of metastasis-associated meningeal fibroblasts (MB-MAFs) in the formation and progression of leptomeningeal metastases.
  • The study aims to identify novel therapeutic targets and strategies for the treatment of leptomeningeal disease in medulloblastoma patients.

Comparative Analysis & Findings

  • The study identifies a targetable intercellular communication cascade involving metastatic cells, meningeal fibroblasts, and bone morphogenetic proteins that contributes to leptomeningeal metastasis.
  • Metastatic cells secrete PDGF ligands to recruit meningeal fibroblasts, which are reprogrammed to become MB-MAFs and promote tumor colonization and growth.
  • Treatment with a PDGF-receptor-alpha neutralizing antibody enhances overall survival in patient-derived xenograft mice, suggesting a potential therapeutic strategy for leptomeningeal disease.

Implications and Future Directions

  • The findings suggest that targeting the intercellular communication cascade between metastatic cells and meningeal fibroblasts may be a promising therapeutic approach for leptomeningeal disease.
  • Future studies could investigate the clinical efficacy of PDGF-receptor-alpha neutralizing antibodies in treating leptomeningeal metastases in medulloblastoma patients.
  • The study's findings may also inform the development of new strategies for identifying and intervening in the metastatic niche to prevent or treat leptomeningeal disease.
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