Publication Date
8-22-2024
Journal
Cell
DOI
10.1016/j.cell.2024.06.011
PMID
38971152
PMCID
PMC11707800
PubMedCentral® Posted Date
1-8-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Humans, Medulloblastoma, Animals, Neoplastic Stem Cells, Mice, Rhombencephalon, Cerebellar Neoplasms, Endothelial Cells, Stem Cell Niche, Stem Cells, Coculture Techniques, Embryonic Structures, Metencephalon, Rhombic lip, cancer genomics, perivascular niche, Group 3 medulloblastoma, brain tumor immunotherapy
Abstract
We identify a population of PRTG+ve MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiate Group 3 Medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem-cells grow adjacent to a human specific interposed vascular plexus in the RLVZ, a phenotype which is recapitulated in Gr3-MB, but not other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem-cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system, or chimeric antigen receptor T-cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting either the PRTGhigh compartment, and/or the perivascular niche represents an approach to treat children with Gr3-MB.
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