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Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics
bioRxiv - Cancer Biology Pub Date : 2020-05-29 , DOI: 10.1101/2020.05.29.123133
Béatrice Cambien , Kevin Lebrigand , Alberto Baeri , Nicolas Nottet , Catherine Compin , Audrey Lamit , Olivier Ferraris , Christophe N Peyrefitte , Virginie Magnone , Jérôme Henriques , Laure-Emmanuelle Zaragosi , Sophie Giorgetti-Peraldi , Frédéric Bost , Marine Gautier-Isola , Roger Rezzonico , Pascal Barbry , Robert Barthel , Bernard Mari , Georges Vassaux

Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types for which human and canine pathologies are closely related at the molecular level. Low-passage, primary carcinoma cells from TNBC versus non-TNBC were used to compare the efficacy of an oncolytic vaccinia virus (VV). We show that non-TNBC cells are 28 times more sensitive to VV than TNBC cells in which VV replication is impaired. Single-cell RNA-seq performed on two different TNBC cell samples infected or not with VV highlighted three distinct populations: naïve cells, bystander cells, defined as cells exposed to the virus but not infected and infected cells. The transcriptome of these three populations showed striking variations in the modulation of pathways regulated by cytokines and growth factors. We hypothesized that the pool of genes expressed in the bystander populations was enriched in antiviral genes. Bio-informatic analysis suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. In addition, we demonstrate experimentally that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, out data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. This information could be used to design new generations of oncolytic poxviruses. Beyond the field of gene therapy, this study demonstrate that single-cell transcriptomics can be used to identify cellular factors influencing viral replication

中文翻译:

用单细胞转录组学鉴定犬高级乳腺肿瘤细胞中的溶瘤疫苗限制因子

乳腺癌,包括三阴性乳腺癌(TNBC),是人类和犬类病理在分子水平上密切相关的肿瘤类型。来自TNBC与非TNBC的低传代原代癌细胞用于比较溶瘤牛痘病毒(VV)的功效。我们显示,非TNBC细胞对VV的敏感性是TNBC细胞的28倍,其中VV复制受损。对被VV感染或未感染VV的两个不同TNBC细胞样品进行的单细胞RNA测序突出了三个不同的种群:幼稚细胞,旁观者细胞,定义为暴露于病毒但未感染和感染的细胞。这三个群体的转录组在细胞因子和生长因子调节的途径的调节中显示出惊人的变化。我们假设在旁观者群体中表达的基因池富含抗病毒基因。生物信息学分析表明,病毒活性降低与细胞的较高间充质状态有关。另外,我们通过实验证明了一个基因DDIT4的高表达对VV的生产是有害的。考虑到DDIT4与包括TNBC在内的各种癌症的不良预后有关,数据突出显示DDIT4是溶瘤痘病毒治疗的候选抗性标记。该信息可用于设计新一代溶瘤痘病毒。除基因治疗领域外,这项研究表明单细胞转录组学可用于鉴定影响病毒复制的细胞因子 生物信息学分析表明,病毒活性降低与细胞的较高间充质状态有关。另外,我们通过实验证明了一个基因DDIT4的高表达对VV的生产是有害的。考虑到DDIT4与包括TNBC在内的各种癌症的不良预后有关,数据突出显示DDIT4是溶瘤痘病毒治疗的候选抗性标记。该信息可用于设计新一代溶瘤痘病毒。除基因治疗领域外,这项研究表明单细胞转录组学可用于鉴定影响病毒复制的细胞因子 生物信息学分析表明,病毒活性降低与细胞的较高间充质状态有关。另外,我们通过实验证明了一个基因DDIT4的高表达对VV的生产是有害的。考虑到DDIT4与包括TNBC在内的各种癌症的不良预后有关,数据突出显示DDIT4是溶瘤痘病毒治疗的候选抗性标记。该信息可用于设计新一代溶瘤痘病毒。除基因治疗领域外,这项研究表明单细胞转录组学可用于鉴定影响病毒复制的细胞因子 我们通过实验证明,一个基因DDIT4的高表达有害于VV的产生。考虑到DDIT4与包括TNBC在内的各种癌症的不良预后有关,数据突出显示DDIT4是溶瘤痘病毒治疗的候选抗性标记。该信息可用于设计新一代溶瘤痘病毒。除基因治疗领域外,这项研究表明单细胞转录组学可用于鉴定影响病毒复制的细胞因子 我们通过实验证明,一个基因DDIT4的高表达有害于VV的产生。考虑到DDIT4与包括TNBC在内的各种癌症的不良预后有关,数据突出显示DDIT4是溶瘤痘病毒治疗的候选抗性标记。该信息可用于设计新一代溶瘤痘病毒。除基因治疗领域外,这项研究表明单细胞转录组学可用于鉴定影响病毒复制的细胞因子
更新日期:2020-05-29
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