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文献精选 > 高引权威"单细胞测序"文献

Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. ​

文献信息 ​

DOI10.1126/science.1254257
PMID24925914
期刊Science (New York, N.Y.)
影响因子45.8
JCR 分区Q1
发表年份2014
被引次数2707
关键词单细胞RNA测序, 胶质母细胞瘤, 肿瘤异质性, 转录程序, 预后
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0036-8075
页码1396-401
期号344(6190)
作者Anoop P Patel, Itay Tirosh, John J Trombetta, Alex K Shalek, Shawn M Gillespie, Hiroaki Wakimoto, Daniel P Cahill, Brian V Nahed, William T Curry, Robert L Martuza, David N Louis, Orit Rozenblatt-Rosen, Mario L Suvà, Aviv Regev, Bradley E Bernstein

一句话小结 ​

本研究通过单细胞RNA测序分析了五个原发性胶质母细胞瘤的430个细胞，发现肿瘤内存在显著的转录程序变异性，并识别出与干性相关的调控因子。此发现揭示了胶质母细胞瘤的生物学、预后和治疗中的重要异质性，为更精准的肿瘤分类和个性化治疗提供了潜在依据。

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单细胞RNA测序 · 胶质母细胞瘤 · 肿瘤异质性 · 转录程序 · 预后

摘要 ​

人类癌症是由具有不同表型、基因型和表观遗传状态的细胞组成的复杂生态系统，但目前的模型并未充分反映患者肿瘤的组成。我们使用单细胞RNA测序（RNA-seq）对来自五个原发性胶质母细胞瘤的430个细胞进行了分析，发现它们在与肿瘤信号传导、增殖、补体/免疫反应和缺氧相关的多种转录程序的表达上存在内在的变异性。我们还观察到一系列与干性相关的表达状态，使我们能够在体内识别出可能的干性调控因子。最后，我们展示了已建立的胶质母细胞瘤亚型分类器在肿瘤内不同细胞中的变异表达，并揭示了这种肿瘤内异质性可能具有的预后意义。因此，我们揭示了在胶质母细胞瘤生物学、预后和治疗中与多种调控程序相关的先前未被充分认识的异质性。

英文摘要 ​

Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.

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主要研究问题 ​

  1. 在单细胞RNA测序中，如何评估不同转录程序对肿瘤微环境的影响？
  2. 除了胶质母细胞瘤，单细胞RNA测序在其他类型癌症中的应用和发现有哪些相似之处？
  3. 该研究中识别的干性调控因子如何影响胶质母细胞瘤的治疗反应？
  4. 在研究肿瘤异质性时，单细胞RNA测序相比于传统方法有哪些优势和局限性？
  5. 如何利用单细胞RNA测序的结果来优化胶质母细胞瘤的个性化治疗方案？

核心洞察 ​

研究背景和目的 ​

人类癌症是由具有不同表型、基因型和表观遗传状态的细胞组成的复杂生态系统，但现有模型未能充分反映患者肿瘤的组成。胶质母细胞瘤（GBM）是一种典型的异质性癌症，具有高度的肿瘤内异质性，这使得传统和靶向疗法难以实现长期缓解。本研究旨在通过单细胞RNA测序技术（scRNA-seq）揭示原发性胶质母细胞瘤中的细胞异质性及其对生物学和治疗的潜在影响。

主要方法/材料/实验设计 ​

研究使用单细胞RNA测序技术分析来自五个原发性胶质母细胞瘤的430个细胞。以下是主要实验设计的流程图：

Mermaid diagram
  1. 样本处理：对新鲜切除的肿瘤进行细胞解离，并去除CD45+细胞以消除免疫细胞的干扰。
  2. RNA测序：对分选出的单细胞进行全长RNA测序，并与群体RNA测序结果进行比较。
  3. 数据分析：采用多维尺度分析、层次聚类等方法分析细胞的转录组异质性。

关键结果和发现 ​

  1. 转录组异质性：研究发现，肿瘤内细胞的转录组表现出显著的异质性，尽管同一肿瘤中的细胞间相关性较高，但不同肿瘤间的细胞表达模式却有交叉。
  2. 信号通路的多样性：在细胞间观察到EGFR、PDGFRA等受体酪氨酸激酶的马赛克表达，表明肿瘤细胞对靶向治疗的潜在抵抗。
  3. 干性状态的梯度：通过构建干性标记基因的表达谱，研究识别出肿瘤内干性细胞的表达梯度，显示出肿瘤内存在不同的干细胞和分化细胞群体。

主要结论/意义/创新性 ​

本研究揭示了胶质母细胞瘤中未被充分认识的细胞异质性，表明肿瘤细胞的转录组、功能和遗传多样性之间的复杂关系。结果表明，肿瘤内的亚型异质性可能对预后有重要影响，并强调了个体化治疗的重要性。

研究局限性和未来方向 ​

  1. 局限性：尽管研究揭示了细胞间的异质性，但对局部微环境及其对细胞状态的影响仍需进一步探讨。
  2. 未来方向：未来研究应集中在肿瘤微环境的空间异质性以及不同细胞状态之间的动态转变，以优化治疗策略。

总结表格 ​

部分内容
研究背景和目的揭示胶质母细胞瘤的细胞异质性及其对生物学和治疗的影响
主要方法单细胞RNA测序，细胞解离与分选，群体RNA测序
关键结果转录组异质性、信号通路多样性、干性状态梯度
主要结论细胞异质性对预后有重要影响，强调个体化治疗的重要性
研究局限性对微环境影响的研究不足
未来方向探讨微环境和细胞状态的动态转变

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引用本文的文献 ​

  1. In vivo models of brain tumors: roles of genetically engineered mouse models in understanding tumor biology and use in preclinical studies. - Iva Simeonova;Emmanuelle Huillard - Cellular and molecular life sciences : CMLS (2014)
  2. MethylPurify: tumor purity deconvolution and differential methylation detection from single tumor DNA methylomes. - Xiaoqi Zheng;Qian Zhao;Hua-Jun Wu;Wei Li;Haiyun Wang;Clifford A Meyer;Qian Alvin Qin;Han Xu;Chongzhi Zang;Peng Jiang;Fuqiang Li;Yong Hou;Jianxing He;Jun Wang;Jun Wang;Peng Zhang;Yong Zhang;Xiaole Shirley Liu - Genome biology (2014)
  3. Are all cancer stem cells created equal? - Xiujie Xie;Theodoros N Teknos;Quintin Pan - Stem cells translational medicine (2014)
  4. Brain tumor cells in circulation are enriched for mesenchymal gene expression. - James P Sullivan;Brian V Nahed;Marissa W Madden;Samantha M Oliveira;Simeon Springer;Deepak Bhere;Andrew S Chi;Hiroaki Wakimoto;S Michael Rothenberg;Lecia V Sequist;Ravi Kapur;Khalid Shah;A John Iafrate;William T Curry;Jay S Loeffler;Tracy T Batchelor;David N Louis;Mehmet Toner;Shyamala Maheswaran;Daniel A Haber - Cancer discovery (2014)
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  10. Cancer genomic research at the crossroads: realizing the changing genetic landscape as intratumoral spatial and temporal heterogeneity becomes a confounding factor. - Shengwen Calvin Li;Lisa May Ling Tachiki;Mustafa H Kabeer;Brent A Dethlefs;Michael J Anthony;William G Loudon - Cancer cell international (2014)

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