Pro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma.
Pro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma.
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DOI：
10.1038/s41467-022-31683-9
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发表时间：
2022-07-08
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
儿科室管膜瘤是一种毁灭性的脑癌，其特点是复发和缺乏有效的化疗方法。这种治疗方法的缺乏是由于对室管膜瘤发生机制的了解有限。通过单核染色质可及性和后颅窝原发肿瘤和远端转移瘤的基因表达谱，我们揭示了与室管膜瘤肿瘤细胞分化为肿瘤衍生细胞系和向间充质样细胞转化相关的关键转录因子和增强子。我们发现NF-κB、AP-1和MYC是这一转变的介质，并表明肿瘤细胞和浸润性小胶质细胞的基因表达谱与这些人群之间丰富的促炎信号是一致的。与这些结果一致的是，转化生长因子-β-1和肿瘤坏死因子-α都能在患者来源的细胞模型上诱导间充质基因的表达，并且转化生长因子-β-1导致了侵袭性表型。综上所述，这些数据表明，炎性细胞因子和氧化应激诱导的肿瘤胶质细胞增生是后颅窝室管膜瘤间质表型的基础。室管膜瘤发生的分子机制尚不清楚。在这里，对后颅窝原发肿瘤和远端转移瘤的单细胞分析强调了促炎细胞因子在促进上皮向间充质转化中的作用。
Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is due to limited knowledge about ependymoma tumorigenic mechanisms. By means of single-nucleus chromatin accessibility and gene expression profiling of posterior fossa primary tumors and distal metastases, we reveal key transcription factors and enhancers associated with the differentiation of ependymoma tumor cells into tumor-derived cell lineages and their transition into a mesenchymal-like state. We identify NFκB, AP-1, and MYC as mediators of this transition, and show that the gene expression profiles of tumor cells and infiltrating microglia are consistent with abundant pro-inflammatory signaling between these populations. In line with these results, both TGF-β1 and TNF-α induce the expression of mesenchymal genes on a patient-derived cell model, and TGF-β1 leads to an invasive phenotype. Altogether, these data suggest that tumor gliosis induced by inflammatory cytokines and oxidative stress underlies the mesenchymal phenotype of posterior fossa ependymoma. The molecular mechanisms underlying ependymoma tumorigenesis remain poorly understood. Here, single cell analysis of posterior fossa primary tumours and distal metastases highlights the role of pro-inflammatory cytokines in promoting epithelial-to-mesenchymal-transition.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
5.3
作者：
Amankulor, Nduka M.;Hambardzumyan, Dolores;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
4.4
作者：
Felmeister, Alex S.;Masino, Aaron J.;Pennington, Jeffrey W.
通讯作者：
Pennington, Jeffrey W.
DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
通讯作者：
Cohen D
影响因子：
46.9
作者：
Bray, Nicolas L.;Pimentel, Harold;Pachter, Lior
通讯作者：
Pachter, Lior