Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma.
Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma.
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DOI：
10.1186/s13059-016-0945-9
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发表时间：
2016-04-29
期刊：
影响因子：
12.3
通讯作者：
Park WY
中科院分区：
文献类型：
--
作者：
Kim KT;Lee HW;Lee HO;Song HJ;Jeong da E;Shin S;Kim H;Shin Y;Nam DH;Jeong BC;Kirsch DG;Joo KM;Park WY
肿瘤内异质性阻碍了基于标记物的抗癌治疗的成功，因为靶向治疗可能消除特定的肿瘤细胞亚群，而使其他细胞不受伤害。因此，最大限度地减少耐药亚群生存的合理策略对于实现长期治疗功效至关重要。利用单细胞RNA测序（RNA-seq），我们研究了一对原发性肾细胞癌及其肺转移瘤的肿瘤内异质性。药物靶向通路的激活表明原发部位和转移部位之间以及每个部位内的单个癌细胞之间存在相当大的变异性。基于对多个药物靶点通路激活的预测，我们推导出一种联合靶向两个相互排斥的通路的转移性癌细胞的组合方案。在体外和体内使用患者来源的异种移植物平台的实验验证中，这种组合策略显示出治疗功效相对于单一疗法显著增加。我们的研究结果证明了单细胞RNA-seq在抗癌方案设计中的研究应用。该方法可以克服阻碍精准医疗成功的肿瘤内异质性。本文的在线版本（doi：10.1186/s13059-016-0945-9）包含补充材料，可供授权用户使用。
Intratumoral heterogeneity hampers the success of marker-based anticancer treatment because the targeted therapy may eliminate a specific subpopulation of tumor cells while leaving others unharmed. Accordingly, a rational strategy minimizing survival of the drug-resistant subpopulation is essential to achieve long-term therapeutic efficacy. Using single-cell RNA sequencing (RNA-seq), we examine the intratumoral heterogeneity of a pair of primary renal cell carcinoma and its lung metastasis. Activation of drug target pathways demonstrates considerable variability between the primary and metastatic sites, as well as among individual cancer cells within each site. Based on the prediction of multiple drug target pathway activation, we derive a combinatorial regimen co-targeting two mutually exclusive pathways for the metastatic cancer cells. This combinatorial strategy shows significant increase in the treatment efficacy over monotherapy in the experimental validation using patient-derived xenograft platforms in vitro and in vivo. Our findings demonstrate the investigational application of single-cell RNA-seq in the design of an anticancer regimen. The approach may overcome intratumoral heterogeneity which hampers the success of precision medicine. The online version of this article (doi:10.1186/s13059-016-0945-9) contains supplementary material, which is available to authorized users.