An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases.
An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases.
复制标题
胶质母细胞瘤辐射抗性的体内模型可鉴定长的非编码RNA和靶向激酶。
DOI：
10.1172/jci.insight.148717
复制
发表时间：
2022-08-22
期刊：
影响因子：
8
通讯作者：
Willey, Christopher D.
中科院分区：
文献类型：
--
作者：
Stackhouse, Christian T.;Anderson, Joshua C.;Yue, Zongliang;Nguyen, Thanh;Eustace, Nicholas J.;Langford, Catherine P.;Wang, Jelai;Rowland, James R.;Xing, Chuan;Mikhail, Fady M.;Cui, Xiangqin;Alrefai, Hasan;Bash, Ryan E.;Lee, Kevin J.;Yang, Eddy S.;Hjelmeland, Anita B.;Miller, C. Ryan;Chen, Jake Y.;Gillespie, Yancey;Willey, Christopher D.
复发性胶质母细胞瘤（GBM）中获得性辐射抗性的关键分子调节因子在很大程度上是未知的，缺乏准确的临床前模型。为了解决这一问题，我们生成了8个获得性放射治疗选择性（RTS）抗性的GBM患者来源的异种移植物（PDX）模型，并与相同患者的未经治疗（放射敏感性; RTU）PDX进行了比较。这些可能独特的模型模拟了连续放射治疗后患者复发性肿瘤的纵向演变。事实上，虽然全外显子组测序显示RTS系中保留了主要的基因组改变，但我们确实在2个RTS模型中检测到与临床GBM复发相关的染色体12 q14扩增。一种潜在的新型生物信息学管道被应用于分析表型、转录组和激酶组学改变，其鉴定了长非编码RNA（lncRNA）和可靶向的PDX特异性激酶。我们在RTS模型中观察到DNA损伤修复途径的差异转录富集，这与几种lncRNA相关。整体kinomic分析分离RTU和RTS模型，但成对分析表明，有多种分子途径获得辐射抗性。鉴定RTS模型特异性激酶，并用临床相关的小分子抑制剂靶向。这组体内RTS患者衍生模型将使未来的临床前治疗测试能够帮助克服GBM患者中观察到的治疗抵抗。
Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy–selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole-exome sequencing showed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that was associated with clinical GBM recurrence in 2 RTS models. A potentially novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic, and kinomic alterations, which identified long noncoding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair pathways in our RTS models, which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation resistance. RTS model–specific kinases were identified and targeted with clinically relevant small molecule inhibitors. This cohort of in vivo RTS patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in patients with GBM.
登录
查看更多内容
候选肿瘤抑制因子 ZNF154 通过 Wnt/β-catenin 信号传导抑制 EMT，从而抑制 NPC 的侵袭和转移
影响因子：
--
作者：
Hu Y;Qi MF;Xu QL;Kong XY;Cai R;Chen QQ;Tang HY;Jiang W
通讯作者：
Jiang W
消除脑肿瘤微环境中辐射诱导的衰老会减轻胶质母细胞瘤的复发。
影响因子：
11.2
作者：
通讯作者：
--
DOI：
10.1056/nejmra0809889
发表时间：
2010-05-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
7
作者：
Buske FA;Bauer DC;Mattick JS;Bailey TL
通讯作者：
Bailey TL
影响因子：
5.7
作者：
Jarboe, John S.;Jaboin, Jerry J.;Willey, Christopher D.
通讯作者：
Willey, Christopher D.