Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state.
Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state.
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DOI：
10.1242/dmm.049754
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发表时间：
2023-12-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
神经母细胞瘤是儿童期最常见的颅外实体瘤，在儿童癌症死亡中占很大比例。先前利用RNA测序对大量肿瘤群体进行的研究表明，两种主要的细胞状态以神经元基因的高表达和低表达为特征。尽管细胞通过改变其基因表达来对治疗作出反应，但尚不清楚这是否反映了不同亚群的平衡变化或单个细胞的可塑性。使用缺乏 MYCN 扩增的小鼠和人类神经母细胞瘤细胞系，我们发现抗原 CD49b（也称为 ITGA2）可以区分这些亚群。 CD49b 表达以不成熟的基因表达程序标记增殖细胞，而 CD49b 阴性细胞表达分化的神经元标记基因并且是非循环的。分类后的群体在培养物中自发地在 CD49b 表达状态之间切换，CD49b 阴性细胞可以在小鼠体内产生快速生长的 CD49b 阳性肿瘤。尽管化疗药物阿霉素治疗选择性地杀死了培养物中的 CD49b 阳性细胞，但当治疗停止后，CD49b 阳性细胞群又恢复了。我们对组蛋白 3 (H3) 赖氨酸 27 乙酰化 (H3K27ac) 进行了分析，以鉴定在每个群体中特异活跃的增强子和超级增强子，并发现 CD49b 阴性细胞在高表达 CD49b 的细胞中活跃的元件处保持了引发 H3 赖氨酸 4 甲基化 (H3K4me1) 标记。因此，引发增强子元件的不当维护可能是神经母细胞瘤细胞可塑性的基础，代表了这种致命肿瘤的潜在治疗靶点。摘要：缺乏 MYCN 扩增的神经母细胞瘤细胞表现出与差异基因表达程序相关的不同亚群，并且可以在以神经元基因表达为特征的状态和去分化状态之间相互转换。
Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant share of childhood cancer deaths. Prior studies utilizing RNA sequencing of bulk tumor populations showed two predominant cell states characterized by high and low expression of neuronal genes. Although cells respond to treatment by altering their gene expression, it is unclear whether this reflects shifting balances of distinct subpopulations or plasticity of individual cells. Using mouse and human neuroblastoma cell lines lacking MYCN amplification, we show that the antigen CD49b (also known as ITGA2) distinguishes these subpopulations. CD49b expression marked proliferative cells with an immature gene expression program, whereas CD49b-negative cells expressed differentiated neuronal marker genes and were non-cycling. Sorted populations spontaneously switched between CD49b expression states in culture, and CD49b-negative cells could generate rapidly growing, CD49b-positive tumors in mice. Although treatment with the chemotherapy drug doxorubicin selectively killed CD49b-positive cells in culture, the CD49b-positive population recovered when treatment was withdrawn. We profiled histone 3 (H3) lysine 27 acetylation (H3K27ac) to identify enhancers and super enhancers that were specifically active in each population and found that CD49b-negative cells maintained the priming H3 lysine 4 methylation (H3K4me1) mark at elements that were active in cells with high expression of CD49b. Improper maintenance of primed enhancer elements might thus underlie cellular plasticity in neuroblastoma, representing potential therapeutic targets for this lethal tumor. Summary: Neuroblastoma cells lacking MYCN amplification exhibit distinct subpopulations associated with differential gene expression programs and can interconvert between a state characterized by expression of neuronal genes and a de-differentiated state.
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影响因子：
5.7
作者：
Okabe A;Kaneda A
通讯作者：
Kaneda A
通过单细胞RNA测序揭示的分子定义的肌神经元类别的多样化。
影响因子：
25
作者：
Morarach K;Mikhailova A;Knoflach V;Memic F;Kumar R;Li W;Ernfors P;Marklund U
通讯作者：
Marklund U
影响因子：
64.5
作者：
Long, Hannah K.;Prescott, Sara L.;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
64.5
作者：
Gosselin D;Link VM;Romanoski CE;Fonseca GJ;Eichenfield DZ;Spann NJ;Stender JD;Chun HB;Garner H;Geissmann F;Glass CK
通讯作者：
Glass CK
影响因子：
16.6
作者：
Helmsauer K;Valieva ME;Ali S;Chamorro González R;Schöpflin R;Röefzaad C;Bei Y;Dorado Garcia H;Rodriguez-Fos E;Puiggròs M;Kasack K;Haase K;Keskeny C;Chen CY;Kuschel LP;Euskirchen P;Heinrich V;Robson MI;Rosswog C;Toedling J;Szymansky A;Hertwig F;Fischer M;Torrents D;Eggert A;Schulte JH;Mundlos S;Henssen AG;Koche RP
通讯作者：
Koche RP