BAG6/CBP/p300-p53 exosomes extracellular vesicles melanoma metastasis
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摘要

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods: Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results: We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6Clow patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion: We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target.

译文

肿瘤细胞释放的细胞外囊泡有助于肿瘤微环境的重编程,并干扰癌症的特征,包括转移。值得注意的是,黑素瘤细胞衍生的 EVs 能够在远处器官建立转移前的利基,或者相反,发挥抗肿瘤活性。然而,关于囊泡如何选择性地包装在定义其特定功能的货物上的分子见解仍然难以捉摸。方法: 在这里,我们研究了分子伴侣 Bcl2-associated anthogene 6 (BAG6,同义词 Bat3) 在促肿瘤和抗肿瘤 EVs 形成中的作用。从野生型细胞和 BAG6-deficient 细胞收集的 EVs 通过质谱和 RNAseq 进行表征。使用 B-16V 移植小鼠黑素瘤模型分析其致瘤潜能。结果: 我们证明了 B-16V 细胞的 EVs 抑制与 Ly6Clow 巡逻单核细胞动员相关的肺转移。这些抗肿瘤 EVs 的形成依赖于 BAG6/CBP/p300-acetylase 复合物对 p53 的乙酰化,随后是运输所需的内体分类复合物成分的募集 (ESCRT) 通过 bag6 的 P (S/T) AP 双基序。BAG6 的基因消融和该通路的破坏导致了一种不同的 EV 亚型的释放,该亚型未能抑制转移,但将促进肿瘤的中性粒细胞招募到转移前的利基。结论: 我们得出结论,BAG6/CBP/p300-p53 轴是指导 EV 货物装载的关键途径,因此是一个潜在的新型微环境治疗靶点。

exosome

肿瘤 肿瘤诊断 临床研究术语
概述  :  

外泌体(Exosome)是由细胞分泌而来的微小囊泡,其中含有与细胞来源相关的蛋白质和RNA等,直径约为30-200 nm,密度在1.13-1.21 g/mL,具有杯状形态、双层膜结构,天然存在于血液、尿液、唾液、母乳和细胞培养基等生物液体中。包括肿瘤细胞在内的几乎所有类型的细胞(免疫细胞、神经细胞、干细胞),都可以产生并释放外泌体。特征和作用作为一种纳米级的膜性囊泡,外泌体在1983年首次被Johnstone等在羊的网织细胞培养液上清中发现并于1989年正式命名。在这之后

exosome

       [遗] 外来体(由多于5种外切酶组成的复合体);外含小体;外泌体

       Exosome can deliver tumor-derived antigens to induce anti-tumor immune responses.  外泌体可传递肿瘤来源的抗原来诱导抗肿瘤的免疫反应。

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