CD44细胞
癌症研究
转移
癌症干细胞
癌症
肺癌
转移抑制因子
医学
乳腺癌
三阴性乳腺癌
克隆(Java方法)
细胞
生物
肿瘤科
内科学
遗传学
DNA
作者
Xia Liu,Valery Adorno-Cruz,Ya-Fang Chang,Yuzhi Jia,Madoka Kawaguchi,Nurmaa K. Dashzeveg,Rokana Taftaf,Erika K. Ramos,Emma J. Schuster,Lamiaa El-Shennawy,Dhwani Patel,Youbin Zhang,Massimo Cristofanilli,Huiping Liu
出处
期刊:Theranostics
[Ivyspring International Publisher]
日期:2021-01-01
卷期号:11 (13): 6632-6643
被引量:65
摘要
Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic breast cancer subtypes lacking targeted therapy. Our recent work demonstrated that circulating tumor cell (CTC) clusters and polyclonal metastasis of TNBC are driven by aggregation of CD44+ cancer stem cells (CSC) and associated with an unfavorable prognosis, such as low overall survival. However, there is no existing therapeutic that can specifically block CTC or CSC cluster formation. Methods: Using patient-derived xenograft (PDX) models, we established an ex vivo tumor cell clustering assay for a pilot screening of blockade antibodies. After identifying EGFR as a target candidate, we modulated the gene expression and inhibited its kinase activity to determine its functional importance in tumor cell clustering and therapeutic inhibition of lung metastasis. We also examined the molecular regulation network of EGFR and a potential connection to CSC marker CD44 and microRNAs, which regulate CTC clustering. Results: We report here that EGFR inhibition successfully blocks circulating CSC (cCSC) clustering and lung metastasis of TNBC. EGFR enhances CD44-mediated tumor cell aggregation and CD44 stabilizes EGFR. Importantly, blocking EGFR by a novel anti-EGFR monoclonal antibody (clone LA1) effectively blocked cell aggregation in vitro and reduced lung metastasis in vivo. Furthermore, our data demonstrated that the tumor suppressor microRNA-30c serves as another negative regulator of cCSC clustering and lung metastasis by targeting CD44 as well as its downstream effector EGFR. Conclusion: Our studies identify a novel anti-EGFR therapeutic strategy to inhibit cCSC aggregation and therefore abolish cCSC cluster-mediated metastasis of TNBC.
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