瑞典乌普萨拉大学Fredrik J. Swartling课题组研究发现，儿童髓母细胞瘤（MB）的干细胞模型显示Oct4/mTOR轴可促进恶性肿瘤的发生。相关论文2019年11月27日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员通过MYCN基因在原始人类后脑来源的神经上皮干细胞（hbNES）或iPSC来源的NES细胞中过表达来产生音猬因子（SHH）-MB亚群的人源化模型，这些细胞在异种移植后会表现出一系列侵袭性表型。iPSC来源的NES肿瘤随着软脑膜的扩散而迅速发展，而hbNES来源的细胞则表现出延迟的肿瘤形成和较少的扩散。甲基化和表达谱分析表明，这两个来源的肿瘤都概括了婴儿SHH MB的特征，并揭示了由于Oct4含量增加而引起的mTOR活化促进了人类SHH肿瘤的侵袭性。靶向mTOR会降低细胞活力并延长生存期，这表明这些不同模型可用于剖析介导肿瘤侵袭的机制，并证明人源化模型对于更好地了解儿科癌症的价值。

据了解， MB是儿童期最常见的恶性脑肿瘤，可能由后脑发育过程中的细胞功能异常引起。

附：英文原文

Title: Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy

Author: Matko aner, Sonja Hutter, Karl O. Holmberg, Gabriela Rosén, Anders Sundstrm, Jignesh Tailor, Tobias Bergstrm, Alexandra Garancher, Magnus Essand, Robert J. Wechsler-Reya, Anna Falk, Holger Weishaupt, Fredrik J. Swartling

Issue&Volume: November 27, 2019

Abstract: Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.

DOI: 10.1016/j.stem.2019.10.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30426-6