Establishment of patient-derived orthotopic xenograft model of 1q+posterior fossa group A ependymoma
Establishment of patient-derived orthotopic xenograft model of 1q+posterior fossa group A ependymoma
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DOI：
10.1093/neuonc/noz116
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发表时间：
2019-12-01
期刊：
影响因子：
15.9
通讯作者：
Griesinger, Andrea M.
中科院分区：
文献类型：
--
作者：
Pierce, Angela M.;Witt, Davis A.;Griesinger, Andrea M.
背景。过去十年中，由于缺乏临床相关模型，伴有 1q (1q+) 染色体增益的儿科后颅窝 A 组 (PFA) 室管膜瘤的治疗并未得到改善。我们描述了第一个 2 个 1q+ PFA 细胞系，它们显着增强了我们对 PFA 肿瘤生物学的理解，并提供了识别特定 1q+ PFA 疗法的工具。然而，细胞系不能准确复制肿瘤微环境。我们目前的目标是建立患者来源的异种移植（PDX）小鼠模型。方法。将 2 名 1q+ PFA 患者的分解肿瘤注射到 NSG 小鼠的胁腹中。然后将侧腹肿瘤移植到 NSG 小鼠的第四脑室或侧脑室中。使用成像、组织学和生物信息学对颅内肿瘤进行表征。结果。 MAF-811_XC 和 MAF-928_XC 在第四脑室内颅内建立，并保留原发性患者肿瘤的组织学、甲基组学和转录组学特征。我们测试了采用分次放疗或化疗治疗 PDX 小鼠的可行性。尽管肿瘤负荷很大，小鼠仍耐受辐射，并且后续成像证实辐射可以减小肿瘤大小。氟尿嘧啶治疗缩小了肿瘤大小，但似乎并未延长生存期。结论。 MAF-811_XC 和 MAF-928_XC 是用于体内研究 1q+ PFA 的新颖、真实且可靠的模型。鉴于对放射的成功反应，这些模型将有利于测试临床相关的联合疗法，以开发针对这一高风险儿科室管膜瘤亚组的未来临床试验。
Background. Treatment for pediatric posterior fossa group A (PFA) ependymoma with gain of chromosome 1q (1q+) has not improved over the past decade owing partially to lack of clinically relevant models. We described the first 2 1q+ PFA cell lines, which have significantly enhanced our understanding of PFA tumor biology and provided a tool to identify specific 1q+ PFA therapies. However, cell lines do not accurately replicate the tumor microenvironment. Our present goal is to establish patient-derived xenograft (PDX) mouse models.Methods. Disaggregated tumors from 2 1q+ PFA patients were injected into the flanks of NSG mice. Flank tumors were then transplanted into the fourth ventricle or lateral ventricle of NSG mice. Characterization of intracranial tumors was performed using imaging, histology, and bioinformatics.Results. MAF-811_XC and MAF-928_XC established intracranially within the fourth ventricle and retained histological, methylomic, and transcriptomic features of primary patient tumors. We tested the feasibility of treating PDX mice with fractionated radiation or chemotherapy. Mice tolerated radiation despite significant tumor burden, and follow-up imaging confirmed radiation can reduce tumor size. Treatment with fluorouracil reduced tumor size but did not appear to prolong survival.Conclusions. MAF-811_XC and MAF-928_XC are novel, authentic, and reliable models for studying 1q+ PFA in vivo. Given the successful response to radiation, these models will be advantageous for testing clinically relevant combination therapies to develop future clinical trials for this high-risk subgroup of pediatric ependymoma.