Early rhombic lip Protogenin^+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

Abstract

We identify a population of Protogenin-positive (PRTG^+ve) MYC^high NESTIN^low stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL^VZ). Oncogenic transformation of early Prtg^+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG^+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RL^VZ, a phenotype that is recapitulated in Gr3-MB but not in 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 PRTG^high 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 RL^VZ PRTG^+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTG^high compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.