Separation of breast cancer and organ microenvironment transcriptomes in metastases
Separation of breast cancer and organ microenvironment transcriptomes in metastases
复制标题
DOI：
10.1186/s13058-019-1123-2
复制
发表时间：
2019-03-06
影响因子：
7.4
通讯作者：
Harrell, J. Chuck
中科院分区：
文献类型：
--
作者：
Alzubi, Mohammad A.;Turner, Tia H.;Harrell, J. Chuck
背景种子和土壤假说是在世纪前提出的，用来描述为什么癌细胞（种子）在某些器官（土壤）中生长。从那时起，定义癌细胞的遗传特性已经得到了大量的研究;然而，器官微环境中介导成功转移生长的基因组介导剂却不太了解。这些研究旨在确定癌症和器官特异性的基因组程序，介导metastasis.MethodsIn这些研究中，一组14人乳腺癌患者来源的异种移植物（PDX）转移模型的开发，然后测试转移向性与两种方法：自发转移的乳腺肿瘤和静脉注射PDX细胞。当作为肿瘤或转移生长时，癌细胞的转录组通过基因组的物种特异性分离与微环境的转录组分离。药物治疗的PDX球体进行，以确定是否在转移中激活的基因可能会识别有针对性的介质violence.ResultsThe实验方法，产生转移的PDX模型进行了鉴定。对134个肿瘤、转移灶和正常非转移性器官进行RNA测序，确定了介导转移的癌症和器官特异性基因组特性。发现肝脏微环境的常见基因组反应发生在对入侵的PDX细胞的反应中。发现癌细胞内的基因要么被微环境短暂调节，要么由于转移性亚系的克隆选择而永久改变。基因集富集分析确定了超过400个基因签名，这些基因签名通常在基底样PDX的转移中被激活。一个Src信号签名被发现广泛上调转移，Src抑制剂被发现是细胞毒性PDX spheroids.ConclusionsThese研究确定，在乳腺癌转移的生长过程中，有基因组的变化，发生在癌细胞和器官微环境。我们假设转移中上调的途径是生存力的介质，并且可能需要同时靶向不同癌细胞途径和/或不同组织区室内的变化来抑制疾病进展。
BackgroundThe seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis.MethodsIn these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability.ResultsThe experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids.ConclusionsThese studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression.