Extracellular vehicles-mediated Twsit1 transferred from tumor cells to brain induces depressive-like behaviors via neuronal morphogenesis.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.112238
Ruo-Si Zou, Jin-Gang He, Yang Zhao, Bing Zhou, Si-Long Deng, Jian-Guo Chen, Fang Wang
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引用次数: 0

Abstract

Rationale: Depression is commonly comorbid with cancer and affects therapeutic efficacy and outcome-of-disease. However, the molecular mechanism underlying cancer-induced depression (CID) remains poorly understood. Twist1 is a proto-oncogene driving tumor progression and metastasis, and chronic stress induces Twist1 expression in the medial prefrontal cortex (mPFC). This study aims to investigate the role and mechanisms of tumor-derived Twist1 in CID. Methods: shTwist1 stably expressing 4T1 cells were obtained through lentivirus transduction and puromycin selection. Tumor cells were subcutaneously inoculated into mice to establish a tumor-bearing mice model. Behavioral assays were used to assess depressive-like behaviors in mice. Ultra-high-speed centrifugation was employed to extract extracellular vehicles (EVs) in 4T1 cell medium or serum from tumor-bearing mice. Quantitative polymerase chain reaction and western blot were used to detect the levels of Twist1 mRNA and protein from tumor-derived EVs or mPFC tissue. Lentivirus was injected into the mPFC to knock down Twist1. Intravenous or intranasal administration of tumor or serum-derived EVs were used to investigate the role of EVs-packaged Twist1 in depressive-like behaviors in mice. Results: The present study demonstrated that tumor-derived EVs mediated the inter-organ communication between tumor cells and brain. Pharmacological inhibition of EVs secretion mitigated depressive-like behaviors in tumor-bearing mice. Intravenous or intranasal injection of EVs from tumor cells or serum from tumor-bearing mice into naïve mice induced a depressive-like phenotype. Further investigation identified tumor-derived EVs Twsit1 as a crucial mediator of cancer-induced dendritic atrophy and depressive-like behaviors in tumor-bearing mice. Knockdown of Twist1 in tumor cells significantly alleviated the detrimental effects of tumor-derived EVs on neuronal morphogenesis and prevented their pro-depressant effects. Conclusions: This study demonstrates that tumor-derived EVs containing Twist1 constitute a key pathological driver of cancer-induced depression, revealing a potential therapeutic target for clinical intervention.

细胞外载体介导的Twsit1从肿瘤细胞转移到大脑通过神经元形态发生诱导抑郁样行为。
理由:抑郁症通常与癌症合并症,影响治疗效果和预后。然而,癌症诱导抑郁(CID)的分子机制仍然知之甚少。Twist1是一种驱动肿瘤进展和转移的原癌基因,慢性应激诱导Twist1在内侧前额叶皮层(mPFC)表达。本研究旨在探讨肿瘤源性Twist1在CID中的作用及其机制。方法:通过慢病毒转导和嘌呤霉素选择获得稳定表达4T1的shTwist1细胞。将肿瘤细胞皮下接种于小鼠,建立荷瘤小鼠模型。行为分析被用来评估老鼠的抑郁样行为。采用超高速离心分离法提取荷瘤小鼠4T1细胞培养基或血清中的细胞外载体(EVs)。采用定量聚合酶链反应和western blot检测肿瘤源性ev或mPFC组织中Twist1 mRNA和蛋白的表达水平。将慢病毒注入mPFC以敲除Twist1。通过静脉或鼻内给药肿瘤或血清源性ev来研究ev包装的Twist1在小鼠抑郁样行为中的作用。结果:本研究证实肿瘤源性ev介导肿瘤细胞与脑的器官间通讯。药理抑制EVs分泌可减轻荷瘤小鼠的抑郁样行为。将来自肿瘤细胞或荷瘤小鼠血清的ev静脉或鼻内注射到naïve小鼠中可诱导抑郁样表型。进一步的研究发现肿瘤来源的EVs Twsit1是肿瘤小鼠癌症诱导的树突萎缩和抑郁样行为的重要介质。在肿瘤细胞中敲低Twist1可显著减轻肿瘤源性ev对神经元形态发生的不利影响,阻止其促抑郁作用。结论:本研究表明,肿瘤来源的含有Twist1的ev是癌症性抑郁的关键病理驱动因素,揭示了临床干预的潜在治疗靶点。
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
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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