Slow-Cycling Cells in Glioblastoma: A Specific Population in the Cellular Mosaic of Cancer Stem Cells.
Slow-Cycling Cells in Glioblastoma: A Specific Population in the Cellular Mosaic of Cancer Stem Cells.
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胶质母细胞瘤中的慢周期细胞：癌症干细胞镶嵌中的特定群体。
DOI：
10.3390/cancers14051126
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发表时间：
2022-02-23
期刊：
影响因子：
5.2
通讯作者：
Deleyrolle LP
中科院分区：
文献类型：
--
作者：
Yang C;Tian G;Dajac M;Doty A;Wang S;Lee JH;Rahman M;Huang J;Reynolds BA;Sarkisian MR;Mitchell D;Deleyrolle LP
成功管理胶质母细胞瘤的一个主要挑战是，我们不了解构成这些肿瘤的细胞的类型和动态行为。结合生物信息学和功能研究，我们描述了存在多个独立的癌症干细胞谱系，驱动胶质母细胞瘤的异质性。我们的研究结果有助于我们解码和映射胶质母细胞瘤细胞的转录和功能多样性。通过揭示肿瘤弹性的潜在机制，即对治疗产生抗性的根源，我们的研究可能会为开发精确有效的治疗脑癌的新策略提供信息。 胶质母细胞瘤（GBM）表现出驱动肿瘤发生、治疗抗性和疾病进展的细胞群。具有这种特性的细胞已被描述为表达特定的表面和细胞内标记物或表现出特定的功能状态，包括慢循环或静止，具有产生增殖后代的能力。在GBM中，这些细胞组分中的每一个都显示出具有癌症干细胞（CSC）的主要特征。在这项研究中，我们专注于这些细胞的比较，并提出了具有干细胞特性的脑癌细胞群体中具有很大表型和功能异质性的证据，特别是慢循环细胞（SCC）和基于常用于富集CSC的标记物表达而表型定义的细胞之间。在这里，我们提出了一个综合分析的异质性存在于GBM癌症干细胞群体使用的方法，包括流式细胞术，批量RNA测序和单细胞转录组学完成功能测定的组合。我们证明，SCC表现出不同范围的典型CSC标志物的表达水平。重要的是，慢循环的性质和这些标志物的表达不是相互包容的。我们询问了单细胞RNA测序数据集，并基于特定代谢特征的最高得分将一组细胞定义为SCC。基于CD133、SOX 2、PTPRZ 1、ITGB 8或CD44的最高表达水平确定多个CSC组。每组由22个细胞组成，显示出有限的细胞重叠，SCC代表一个独特的群体，22个细胞中没有一个被包括在其他组中。我们还发现了群体之间的转录组学差异，这与GBM的临床病理特征相关。具有强SCC特征评分的患者与较短的生存期相关，并聚集在间充质分子亚型内。这些群体中的细胞多样性在功能上也得到了证明，正如对化疗药物替莫唑胺的异质性反应所说明的那样。总之，我们的研究支持癌症干细胞镶嵌模型，慢循环细胞代表具有播散细胞关键特征的关键元素。
A major challenge in successfully managing glioblastoma is that we do not understand the types and dynamic behaviors of the cells that constitute these tumors. Combining bioinformatics and functional studies, we describe the presence of multiple independent lineages of cancer stem cells driving the heterogeneic nature of glioblastoma. Our results help us decode and map the transcriptional and functional diversity of glioblastoma cells. By revealing potential mechanisms underlying tumor resilience, the root of resistance to treatment, our study may inform novel strategies to develop precision and effective therapies to treat brain cancer. Glioblastoma (GBM) exhibits populations of cells that drive tumorigenesis, treatment resistance, and disease progression. Cells with such properties have been described to express specific surface and intracellular markers or exhibit specific functional states, including being slow-cycling or quiescent with the ability to generate proliferative progenies. In GBM, each of these cellular fractions was shown to harbor cardinal features of cancer stem cells (CSCs). In this study, we focus on the comparison of these cells and present evidence of great phenotypic and functional heterogeneity in brain cancer cell populations with stemness properties, especially between slow-cycling cells (SCCs) and cells phenotypically defined based on the expression of markers commonly used to enrich for CSCs. Here, we present an integrative analysis of the heterogeneity present in GBM cancer stem cell populations using a combination of approaches including flow cytometry, bulk RNA sequencing, and single cell transcriptomics completed with functional assays. We demonstrated that SCCs exhibit a diverse range of expression levels of canonical CSC markers. Importantly, the property of being slow-cycling and the expression of these markers were not mutually inclusive. We interrogated a single-cell RNA sequencing dataset and defined a group of cells as SCCs based on the highest score of a specific metabolic signature. Multiple CSC groups were determined based on the highest expression level of CD133, SOX2, PTPRZ1, ITGB8, or CD44. Each group, composed of 22 cells, showed limited cellular overlap, with SCCs representing a unique population with none of the 22 cells being included in the other groups. We also found transcriptomic distinctions between populations, which correlated with clinicopathological features of GBM. Patients with strong SCC signature score were associated with shorter survival and clustered within the mesenchymal molecular subtype. Cellular diversity amongst these populations was also demonstrated functionally, as illustrated by the heterogenous response to the chemotherapeutic agent temozolomide. In conclusion, our study supports the cancer stem cell mosaicism model, with slow-cycling cells representing critical elements harboring key features of disseminating cells.
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影响因子：
46.9
作者：
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