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通过促进免疫抑制瘤微环境,TAZ促进乳腺瘤的生长

Anat Gershoni¹, Ori Hassin¹, Nishanth Belugali Nataraj²

¹Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Molecular oncology

|September 16, 2023

概括

WWTR1 (TAZ) 通过抑制抗瘤免疫力来促进三阴性乳腺癌的生长. 在小鼠模型中减少TAZ减少了瘤大小,并改变了免疫微环境,突出TAZ.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

河马通路的核心激酶级联抑制了YAP和WWTR1 (TAZ),这是关键的转录协活性剂.
乳腺癌中常见的Hippo通路的下调导致YAP/TAZ活动诱导.
WWTR1 (TAZ) 被认为是乳腺癌进展中的潜在瘤基因.

研究的目的:

研究WWTR1 (TAZ) 在三阴性乳腺癌 (TNBC) 发病过程中的特定作用.
阐明TAZ影响瘤免疫微环境和瘤生长的机制.

主要方法:

在使用CRISPR/Cas9和shRNA的小鼠TNBC 4T1细胞中减少TAZ.
在小鼠体内注射TAZ枯竭和对照细胞,然后对瘤生长进行监测.
通过瘤和培养细胞的RNA测序 (RNA-seq) 进行基因表达概况.
使用瘤切片染色和CyTOF进行调控性T细胞 (Treg) 量化,对RNA-seq发现的实验验证.
条件介质的细胞因子阵列分析,以确定TAZ调节的分泌因子.

主要成果:

在体内,TAZ枯竭显著减少了瘤大小,支持其致癌作用.
RNA-seq分析揭示了TAZ-依赖的"炎症反应"途径的丰富.
在瘤中,TAZ缺乏导致调节性T细胞 (Tregs) 的显著枯竭.
免疫缺陷小鼠的瘤生长差异被消除了,这强调了TAZ的免疫调节功能.
TAZ增加了包括PAI-1,WISP-1和IL-23在内的细胞因子的分泌,这表明免疫调节的机制.

结论:

WWTR1 (TAZ) 功能非细胞自主,促进三阴性乳腺癌的生长.
TAZ通过抑制抗瘤免疫反应,特别是Treg透来改变瘤免疫微环境.
在这种情况下,TAZ的致癌活性严重依赖于其免疫调节能力.

关键词:

河马的路径河马的路径塔兹塔兹是什么意思?这是Tregs.乳腺癌乳腺癌乳腺癌

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