MEOX2 homeobox gene promotes growth of malignant gliomas [RNA-Seq]. MEOX2 homeobox gene promotes growth of malignant gliomas [RNA-Seq]

Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10 and aberrantly activated RTK signaling pathways. Here, we identify mesenchymal homeobox 2 (MEOX2) as a salient oncogenic transcription factor candidate with increased expression in GBMs. Our results suggest that MEOX2 can enhance ERK signaling through a feed-forward mechanism. We show that MEOX2 overexpression can lead to increased growth in bona fide GBM implantation models and cooperates with loss of p53 and PTEN in cerebral organoid models of human malignant gliomas to induce cell proliferation. Furthermore, using high-throughput genomics, we identify transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. Overall design: Examination of transcriptomic alterations assciated with MEOX2 loss (using CRISPR/Cas9 in patient-derived GBM tumorspheres) or overexpression (in patient-derived GBM tumorspheres and immortalized human astrocytes).

胶质母细胞瘤（Glioblastoma, GBM）是一类侵袭性极强的肿瘤，常伴随7号染色体扩增、10号染色体缺失以及受体酪氨酸激酶（RTK）信号通路异常激活。本研究鉴定出间充质同源框2（mesenchymal homeobox 2, MEOX2）作为一类显著的致癌转录因子候选靶点，其在GBM组织中表达上调。研究结果表明，MEOX2可通过前馈机制增强细胞外调节蛋白激酶（ERK）信号通路。实验证实，MEOX2过表达可在真实GBM移植模型中促进肿瘤生长，并在人类恶性胶质瘤大脑类器官模型中与p53及PTEN缺失协同诱导细胞增殖。此外，本研究借助高通量基因组学技术，在患者来源的GBM肿瘤球模型及新鲜冰冻GBM组织中鉴定出MEOX2的转录靶基因。实验设计概述：检测与MEOX2敲除（采用CRISPR/Cas9技术在患者来源的GBM肿瘤球中）或过表达（在患者来源的GBM肿瘤球及永生化人星形胶质细胞中）相关的转录组改变。