The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Genomics and Development of Childhood Cancers, Institut Curie, PSL University, 75005 Paris, France; INSERM U830, Cancer Heterogeneity Instability and Plasticity, Institut Curie, PSL University, 75005 Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, 75005 Paris, France.
Cell. 2024 Aug 22;187(17):4733-4750.e26. doi: 10.1016/j.cell.2024.06.011. Epub 2024 Jul 5.
We identify a population of Protogenin-positive (PRTG) MYC NESTIN stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL). Oncogenic transformation of early Prtg rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG stem cells grow adjacent to a human-specific interposed vascular plexus in the RL, 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 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 PRTG stem cells inhabiting a specific perivascular niche. Targeting the PRTG compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.
我们在四周大的人类胚胎后脑中鉴定出一群 Protogenin 阳性（PRTG）的 MYC NESTIN 干细胞，它们随后定位于菱形唇（RL）的室管膜区。早期 Prtg 菱形唇干细胞的致癌转化引发了 3 组髓母细胞瘤（Gr3-MB）样肿瘤。PRTG 干细胞在 RL 中与一个人类特异性的插入血管丛相邻生长，这种表型在 Gr3-MB 中重现，但在其他类型的髓母细胞瘤中没有重现。Gr3-MB 与内皮细胞共培养促进肿瘤干细胞生长，内皮细胞呈现未成熟表型。使用白喉毒素系统或嵌合抗原受体 T 细胞在体内靶向 Gr3-MB 的 PRTG 隔室构成有效的治疗方法。人类 Gr3-MB 可能来自早期胚胎 RL PRTG 干细胞，它们栖息在特定的血管周围龛位中。靶向 PRTG 隔室和/或血管周围龛位代表了一种治疗 Gr3-MB 儿童的方法。
