Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest.
Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest.
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DOI：
10.1016/j.stemcr.2015.09.014
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发表时间：
2015-11-10
影响因子：
5.9
通讯作者：
Pollard SM
中科院分区：
文献类型：
--
作者：
Carén H;Stricker SH;Bulstrode H;Gagrica S;Johnstone E;Bartlett TE;Feber A;Wilson G;Teschendorff AE;Bertone P;Beck S;Pollard SM
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，其生长由干细胞样细胞驱动。BMP信号触发GBM干细胞（GSC）的细胞周期退出和分化，因此可能具有治疗价值。然而，伴随分化的表观遗传机制仍然不清楚。目前还不清楚细胞周期停滞是否是终端。在这里，我们发现只有一个子集的GSC文化表现出星形胶质细胞分化的BMP。虽然产生了明显分化的非周期性星形胶质细胞，但它们仍然容易受到细胞周期重新进入的影响，并且不能适当地重新配置DNA甲基化模式。染色质可及性映射确定的位点，未能改变BMP的反应，这些都是丰富的SOX转录因子结合基序。SOX转录因子，因此，可能会限制分化承诺。在GSC衍生的少突胶质细胞样细胞中观察到类似的细胞周期再进入和去分化倾向。这些发现突出了BMP诱导分化作为GBM治疗的显著障碍。全基因组分析显示胶质母细胞瘤（GBM）分化期间的DNA甲基化模式GBM干细胞响应于BMP SOX转录因子而出现延迟和不完全的表观遗传变化可以解释缺乏终末分化缺乏分化定型限制了基于BMP的疗法的有效性BMP诱导胶质母细胞瘤干细胞（GSC）的分化，但仍不清楚是否发生分化定型和永久性细胞周期停滞。Pollard，Beck及其同事报告说，GSC的分化后代无法重新配置DNA甲基化模式，并且容易发生去分化。未能抑制SOX转录因子的活性可以解释这种缺陷。
Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stem cell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stem cells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Here we find only a subset of GSC cultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy for GBM. Genome-wide profiling shows DNA methylation patterns during glioblastoma (GBM) differentiation Delayed and incomplete epigenetic changes appear in GBM stem cells in response to BMP SOX transcription factors may explain the lack of terminal differentiation Lack of differentiation commitment limits the effectiveness of BMP-based therapies BMP induces differentiation of glioblastoma stem cells (GSCs), but it remains unclear if differentiation commitment and permanent cell-cycle arrest occurs. Pollard, Beck, and colleagues report that differentiated progeny of GSCs fail to reconfigure DNA methylation patterns and are vulnerable to de-differentiation. Failure to suppress the activity of SOX transcription factors may explain this deficit.