Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells.
Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells.
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转录组变异而非基因组变异赋予乳腺癌干细胞表型
DOI：
10.1186/s40880-018-0326-8
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发表时间：
2018-09-19
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Tong M;Deng Z;Yang M;Xu C;Zhang X;Zhang Q;Liao Y;Deng X;Lv D;Zhang X;Zhang Y;Li P;Song L;Wang B;Al-Dherasi A;Li Z;Liu Q
背景乳腺癌干细胞（BCSCs）被认为是肿瘤复发和耐药的主要原因.了解BCSC的特性可能会为乳腺癌治疗开辟新的途径。虽然已经在BCSC表征方面取得了一些发现，但BCSC起源的关键因素在很大程度上尚不清楚。本研究旨在确定基因组突变是否有助于获得癌干细胞样表型，并调查BCSCs.MethodsWe的遗传和转录特征检测潜在的BCSC表型相关的突变热点区域，通过使用全基因组测序亲本癌细胞和衍生的连续世代球在BCSC频率增加的顺序，然后在批量细胞和单细胞水平上进行靶深度DNA测序。为了确定与BCSC，散装细胞和单细胞RNA测序进行了相关的转录程序。ResultsBy使用散装细胞的全基因组测序，检测到潜在的BCSC表型相关的突变热点区域。通过靶向深度DNA测序的验证，在批量细胞和单细胞水平上，均未发现与BCSC表型特异性相关的遗传变化。此外，单细胞RNA测序显示，在单细胞水平上癌细胞中存在显著的转录组变异性，这预测了BCSC的特征。值得注意的是，在74个基因的转录过程中，这种转录组变异性被富集，显示为BCSC标记。复发风险高的乳腺癌患者表现出更高的表达水平，这些BCSC标志物比那些复发风险低，从而突出这些BCSC marker.ConclusionsTranscriptomic变异，而不是基因突变，预测乳腺癌预后的临床意义，区分BCSC从非BCSC。所鉴定的74个BCSC标志物有可能成为乳腺癌治疗的新靶点。
BackgroundBreast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSC characterization, the factors critical to the origination of BCSCs are largely unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.MethodsWe detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency, and then performed target deep DNA sequencing at bulk-cell and single-cell levels. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing was performed.ResultsBy using whole-genome sequencing of bulk cells, potential BCSC phenotype-associated mutation hotspot regions were detected. Validation by target deep DNA sequencing, at both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features. Notably, this transcriptomic variability was enriched during the transcription of 74 genes, revealed as BCSC markers. Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse, thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.ConclusionsTranscriptomic variability, not genetic mutations, distinguishes BCSCs from non-BCSCs. The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.
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影响因子：
37.3
作者：
Botchkina GI;Zuniga ES;Das M;Wang Y;Wang H;Zhu S;Savitt AG;Rowehl RA;Leyfman Y;Ju J;Shroyer K;Ojima I
通讯作者：
Ojima I
影响因子：
3.9
作者：
Gökmen-Polar Y;Goswami CP;Toroni RA;Sanders KL;Mehta R;Sirimalle U;Tanasa B;Shen C;Li L;Ivan M;Badve S;Sledge GW Jr
通讯作者：
Sledge GW Jr
影响因子：
9.2
作者：
Boo L;Ho WY;Ali NM;Yeap SK;Ky H;Chan KG;Yin WF;Satharasinghe DA;Liew WC;Tan SW;Ong HK;Cheong SK
通讯作者：
Cheong SK
影响因子：
45.3
作者：
Dave, Bhuvanesh;Migliaccio, Ilenia;Chang, Jenny C.
通讯作者：
Chang, Jenny C.
影响因子：
1.9
作者：
Du, Caiwen;Wen, Bogui;Wu, Mingyao
通讯作者：
Wu, Mingyao