The metalloproteinase ADAMDEC1 maintains a novel growth factor signalling loop in glioblastoma cancer stem cells
The metalloproteinase ADAMDEC1 maintains a novel growth factor signalling loop in glioblastoma cancer stem cells
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金属蛋白酶 ADAMDEC1 在胶质母细胞瘤干细胞中维持新的生长因子信号环路
DOI：
10.1093/neuonc/noz167.003
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发表时间：
2019
期刊：
影响因子：
15.9
通讯作者：
Jimenez-Pascual A
中科院分区：
文献类型：
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作者：
Jimenez-Pascual A
表观遗传调节因子Bmi 1对神经干细胞（NSC）的自我更新至关重要，并且在胶质母细胞瘤（GBM）干细胞/起始细胞（GIC）中高度表达，其中敲低显著降低异种移植模型中的肿瘤生长。我们已经使用了一个组合的全基因组和靶基因驱动的方法，以确定EphrinA 5（EfnA 5）作为介导的Bmi 1功能在小鼠和人类GIC.Methods和resultsWe比较mGIC，从aPTEN/p53缺失小鼠模型，匹配的NSC。ChIPSeq和RNASeq的组合显示了抑制性PRC标记H3 K27 me 3在mGIC中的差异再分布，并且转录调节在一定比例的H3 K27 me 3标记基因中是Bmi 1依赖性的。随后，使用shRNA敲除，我们表明Bmi 1通过抑制mGIC中的EfnA 5来调节细胞形态、增殖和迁移/侵袭，并且相同的机制对于同种异体移植模型中的GBM发育是必不可少的。为了证实BMI 1/EFNA 5通路的翻译潜力，我们检查了已发表的RNA微阵列、RNAseq和单细胞RNAseq数据集，发现BMI 1和EFNA 5之间存在显著的反比关系。最后，我们表明，BMI 1还通过抑制EFNA 5在原代人GICin vitro.ConclusionsWe目前的证据，从小鼠模型，人类表达数据集和人类原代细胞显示，BMI 1-EfnA 5通路发挥了突出的调节作用，在GIC细胞增殖。由于BMI 1沉默的抗增殖作用是由hGIC中EFNA 5的去抑制介导的，因此，例如用模拟EFNA 5作用的试剂精确靶向肝配蛋白信号传导，可能是过表达BMI 1的人GBM中的有效治疗工具。
IntroductionThe epigenetic regulator Bmi1 is essential for the self-renewal of neural stem cells (NSC), and highly expressed in glioblastoma (GBM) stem/initiating cells (GIC), where knockdown significantly reduces tumour growth in xenograft models. We have used a combined genome-wide and target gene-driven approach to identify EphrinA5 (EfnA5) as a mediator of Bmi1 function in mouse and human GIC.Methods and resultsWe compared mGIC, from aPTEN/p53deletion mouse model, to matched NSC. Combined ChIPSeq and RNASeq showed a differential redistribution of the repressive PRC mark H3K27me3 in mGIC, and that transcriptional regulation is Bmi1-dependent in a proportion of H3K27me3 marked genes. Subsequently, using shRNA knockdown, we show that Bmi1 regulates cell morphology, proliferation and migration/invasion via repression of EfnA5 in mGIC, and that the same mechanism is essential for GBM development in an allograft model. To confirm the translational potential of the BMI1/EFNA5 pathway we examined published RNA microarray, RNAseq and single-cell RNAseq datasets and found a significant inverse relationship between BMI1 and EFNA5. Finally, we show that BMI1 also regulates cell proliferation via repression of EFNA5 in primary human GICin vitro.ConclusionsWe present evidence from a mouse model, human expression datasets and human primary cells showing that the Bmi1-EfnA5 pathway plays a prominent regulatory role in GIC. As the anti-proliferative role of BMI1 silencing is mediated by de-repression of EFNA5 in hGIC, precision targeting of Ephrin signalling, for example with agents that mimic EFNA5 action, could be an effective therapeutic tool in human GBM overexpressing BMI1.