Metastasis-Specific Gene Expression in Autochthonous and Allograft Mouse Mammary Tumor Models: Stratification and Identification of Targetable Signatures.
Metastasis-Specific Gene Expression in Autochthonous and Allograft Mouse Mammary Tumor Models: Stratification and Identification of Targetable Signatures.
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自体和同种异体移植小鼠乳腺肿瘤模型中的转移特异性基因表达：可靶向特征的分层和鉴定。
DOI：
10.1158/1541-7786.mcr-20-0046
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Hunter,KentW
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文献类型：
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作者：
Ross,Christina;Szczepanek,Karol;Lee,Maxwell;Yang,Howard;Peer,CodyJ;Kindrick,Jessica;Shankarappa,Priya;Lin,Zhi-Wei;Sanford,JackD;Figg,WilliamD;Hunter,KentW
乳腺癌转移是美国女性癌症相关死亡的主要原因。推进转移靶向干预的障碍是原发性和继发性病变之间的表型异质性。为了鉴定转移特异性基因表达谱，我们对乳腺癌小鼠模型进行了RNA测序;分析了来自各种驱动因素和途径的模型的转移。我们对比了这些模型，并确定了常见的、可针对的特征。同种异体移植模型比基因工程小鼠模型（GEMM）表现出更多的间充质样基因表达，并且GEMM来源的转移组织的原代培养诱导了间充质样基因表达。此外，转移特异性转录组在相同细胞系的尾静脉和原位注射之间不同。自发转移模型的常见基因表达包括西地那非反应和尼古丁降解途径。引人注目的是，体内西地那非治疗显著降低了54%的转移，而尼古丁显著增加了46%的转移。这些数据表明，（i）可操作的转移特异性途径可以很容易地确定，（ii）现有药物可能具有很大的潜力，以减轻转移的发生率，和（iii）转移可能会受到生活方式的选择，如选择消费尼古丁产品的影响很大。总之，虽然小鼠模型的乳腺癌转移的方式不同，不容忽视，有共同的特点，可以确定和潜在的治疗目标。mcr.aacrjournals.org/content/molcanres/18/9/1278/F1.large.jpg
Breast cancer metastasis is a leading cause of cancer-related death of women in the United States. A hurdle in advancing metastasis-targeted intervention is the phenotypic heterogeneity between primary and secondary lesions. To identify metastasis-specific gene expression profiles we performed RNA-sequencing of breast cancer mouse models; analyzing metastases from models of various drivers and routes. We contrasted the models and identified common, targetable signatures. Allograft models exhibited more mesenchymal-like gene expression than genetically engineered mouse models (GEMM), and primary culturing of GEMM-derived metastatic tissue induced mesenchymal-like gene expression. In addition, metastasis-specific transcriptomes differed between tail vein and orthotopic injection of the same cell line. Gene expression common to models of spontaneous metastasis included sildenafil response and nicotine degradation pathways. Strikingly,in vivosildenafil treatment significantly reduced metastasis by 54%, while nicotine significantly increased metastasis by 46%. These data suggest that (i) actionable metastasis-specific pathways can be readily identified, (ii) already available drugs may have great potential to alleviate metastatic incidence, and (iii) metastasis may be influenced greatly by lifestyle choices such as the choice to consume nicotine products. In summary, while mouse models of breast cancer metastasis vary in ways that must not be ignored, there are shared features that can be identified and potentially targeted therapeutically.ImplicationsThe data we present here exposes critical variances between preclinical models of metastatic breast cancer and identifies targetable pathways integral to metastatic spread.Visual Overviewhttp://mcr.aacrjournals.org/content/molcanres/18/9/1278/F1.large.jpg.