NUPR1 packaged in extracellular vesicles promotes murine triple-negative breast cancer in a type 1 interferon-independent manner

Angelica Ortiz, Aikaterini Stavrou, Shan Liu, Danqi Chen, Steven S. Shen, Chunyuan Jin
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Abstract

Aim: This study aims to elucidate the involvement of triple-negative breast cancer (TNBC)-derived extracellular vesicles in metastasis. The loss of components in the type 1 interferon (IFN1) signaling pathway has been linked to the promotion of metastasis. However, IFN1 signaling induces immunological dormancy and promotes tumorigenesis. Our hypothesis was that TNBC cells release tumor-derived extracellular vesicles (TEVs) that promote metastasis in an IFN1-independent manner. Methods: Two murine TNBC models and transgenic mice were used to examine the role of IFN1 in TNBC progression to metastasis. Reserpine was employed to determine the effect of TEV education on TNBC progression and overall survival. EVs from cancer cells treated with vehicle and reserpine and from the serum of tumor-bearing mice receiving reserpine were examined to determine changes in EV release and EV content. Results: TNBC cells progress to metastasis in mice lacking the IFN1-induced gene cholesterol-25 hydroxylase (CH25H) or expressing the IFNAR1S526 knock-in that cannot be downregulated. Reserpine suppresses EV release from TNBC cells in vitro and in vivo . Western blot analysis demonstrated reserpine decreased NUPR1 protein levels in EVs. RNAseq analysis demonstrated that endothelial cells lacking CH25H treated with TEVs exhibited increased NUPR1 expression that was decreased by adding reserpine with the TEVs. NUPR1 overexpression upregulated genes that mediate TEV biogenesis and incorporation. Knockdown of NUPR1 with shRNA decreased the release of TEVs. Conclusion: In conclusion, our study suggests that TNBC is driven by aberrant packaging of NUPR1 into TEVs which were transferred into recipient cells to activate pro-metastatic transcription driven by NUPR1.
包裹在细胞外囊泡中的 NUPR1 以与 1 型干扰素无关的方式促进小鼠三阴性乳腺癌的发生
目的:本研究旨在阐明三阴性乳腺癌(TNBC)产生的细胞外囊泡参与转移的情况。1型干扰素(IFN1)信号通路中成分的缺失与促进转移有关。然而,IFN1 信号诱导免疫休眠并促进肿瘤发生。我们的假设是,TNBC细胞释放的肿瘤衍生胞外囊泡(TEVs)会以不依赖IFN1的方式促进转移。研究方法使用两种小鼠 TNBC 模型和转基因小鼠来研究 IFN1 在 TNBC 转移过程中的作用。采用瑞瑟平确定 TEV 教育对 TNBC 进展和总生存期的影响。研究人员检测了用载体和利舍平处理的癌细胞中的EV,以及接受利舍平治疗的肿瘤小鼠血清中的EV,以确定EV释放和EV含量的变化。结果TNBC细胞在缺乏IFN1诱导基因胆固醇-25羟化酶(CH25H)或表达无法被下调的IFNAR1S526基因敲入的小鼠体内发生转移。Reserpine 可抑制 TNBC 细胞在体外和体内的 EV 释放。Western 印迹分析表明,利舍平降低了 EV 中的 NUPR1 蛋白水平。RNAseq 分析表明,用 TEVs 处理缺乏 CH25H 的内皮细胞会增加 NUPR1 的表达,而在 TEVs 中添加瑞舍平可降低 NUPR1 的表达。NUPR1 的过表达上调了介导 TEV 生物发生和整合的基因。用 shRNA 敲除 NUPR1 可减少 TEV 的释放。结论总之,我们的研究表明,TNBC是由NUPR1异常包装成TEVs驱动的,TEVs被转移到受体细胞中,激活由NUPR1驱动的促转移转录。
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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