The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype.

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-04 DOI:10.1242/dmm.050771
Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp
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引用次数: 0

Abstract

Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin (also known as Cdh1) and upregulation of mesenchymal markers such as N-cadherin (Cdh2) and vimentin (Vim). Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines 4T07, 168FARN and 67NR. We found that 4T1 cells display a hybrid epithelial/mesenchymal phenotype with co-expression of epithelial and mesenchymal markers, whereas 4T07, 168FARN, and 67NR cells display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid epithelial/mesenchymal phenotype that promotes invasion and metastasis.

高度转移的 4T1 乳腺癌模型具有上皮-间充质混合表型的特征。
上皮-间质转换(EMT)被认为是通过下调 E-粘连蛋白和上调间质标记(如 N-粘连蛋白和波形蛋白)来促进转移的。与此相反,E-cadherin 在许多侵袭性癌中得以保留,并促进了细胞的集体侵袭。为了研究 E-cadherin如何调控转移,我们研究了高转移性、E-cadherin 阳性的小鼠 4T1 乳腺癌模型,以及转移性较低、与 4T1 相关的细胞系 4T07、168FARN 和 67NR。我们发现 4T1 细胞显示出混合-E/M 表型,同时表达上皮和间质标记,而 4T07、168FARN 和 67NR 在体外显示出逐渐增多的间质表型,这与其体内转移能力成反比。我们利用 RNA 干扰和组成型表达证明,E-cadherin 的表达水平并不能决定 4T1 或 4T07 细胞在小鼠体内的转移能力。从机理上讲,4T1 细胞具有高度动态、不稳定的细胞-细胞连接,可以在不下调 E-cadherin 的情况下发生集体侵袭。然而,体内的 4T1 正位肿瘤也包含类似 EMT 的 E-cadherin 缺失亚区。因此,4T1细胞可作为具有促进侵袭和转移的混合E/M表型的癌症模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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