Mechanism of efficacy of trabectedin against myxoid liposarcoma entails detachment of the FUS-DDIT3 transcription factor from its DNA binding sites.

IF 11.4 1区医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2024-11-26 DOI:10.1186/s13046-024-03228-z

Ilaria Craparotta, Laura Mannarino, Riccardo Zadro, Sara Ballabio, Sergio Marchini, Giulio Pavesi, Marta Russo, Salvatore Lorenzo Renne, Marina Meroni, Marianna Ponzo, Ezia Bello, Roberta Sanfilippo, Paolo G Casali, Maurizio D'Incalci, Roberta Frapolli

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Abstract

Background: The marine drug trabectedin has shown unusual effectiveness in the treatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the expression of the FUS-DDIT3 chimera. Trabectedin elicits a significant transcriptional response in MLPS resulting in cellular depletion and reactivation of adipogenesis. However, the role of the chimeric protein in the mechanism of action of the drug is not entirely understood.

Methods: FUS-DDIT3-specific binding sites were assessed through Chromatin Immunoprecipitation Sequencing (ChIP-Seq). Trabectedin-induced effects were studied on pre-established patient-derived xenograft models of MLPS, one sensitive to (ML017) and one resistant against (ML017ET) trabectedin at different time points (24 and 72 h, 15 days). Data were integrated with RNA-Seq from the same models.

Results: Through ChIP-Seq, here we demonstrate that trabectedin inhibits the binding of FUS-DDIT3 to its target genes, restoring adipocyte differentiation in a patient-derived xenograft model of MLPS sensitive to trabectedin. In addition, complementary RNA-Seq data on the same model demonstrates a two-phase effect of trabectedin, characterized by an initial FUS-DDIT3-independent cytotoxicity, followed by a transcriptionally active pro-differentiation phase due to the long-lasting detachment of the chimera from the DNA. Interestingly, in a trabectedin-resistant MLPS model, the effect of trabectedin on FUS-DDIT3 rapidly decreased over time, and prolonged treatment was no longer able to induce any transcription or post-transcriptional modifications.

Conclusions: These findings explain the unusual mechanism underlying trabectedin's effectiveness against MLPS by pinpointing the chimera's role in inducing the differentiation block responsible for MLPS pathogenesis. Additionally, the findings hint at a potential mechanism of resistance acquired in vivo.

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曲贝替丁（Trabectedin）对类肌脂肪肉瘤的疗效机制是使 FUS-DDIT3 转录因子脱离其 DNA 结合位点。

背景：海洋药物曲贝替丁（Trabectedin）在治疗类粘液性脂肪肉瘤（MLPS）方面显示出不同寻常的疗效，MLPS是一种以表达FUS-DDIT3嵌合体为特征的脂肪肉瘤。曲贝替丁（Trabectedin）能在 MLPS 中引起明显的转录反应，导致细胞耗竭和脂肪生成的重新激活。然而，嵌合蛋白在药物作用机制中的作用还不完全清楚：方法：通过染色质免疫沉淀测序（ChIP-Seq）评估了FUS-DDIT3特异性结合位点。在不同的时间点（24 和 72 小时，15 天），对已建立的 MLPS 患者异种移植模型（一种对 ML017 敏感，一种对 ML017ET 耐药）进行了曲贝替定诱导效应的研究。数据与来自相同模型的 RNA-Seq 数据进行了整合：结果：通过 ChIP-Seq，我们证明了曲贝替定抑制了 FUS-DDIT3 与其靶基因的结合，从而恢复了对曲贝替定敏感的 MLPS 患者来源异种移植模型的脂肪细胞分化。此外，关于同一模型的互补 RNA-Seq 数据显示了曲贝替丁（trabectedin）的两阶段效应，其特点是最初的 FUS-DDIT3 细胞毒性不依赖于 FUS-DDIT3，随后由于嵌合体与 DNA 的持久分离，转录活跃的促分化阶段随之而来。有趣的是，在曲贝替定耐药的MLPS模型中，曲贝替定对FUS-DDIT3的作用随着时间的推移迅速减弱，长期治疗不再能诱导任何转录或转录后修饰：这些发现解释了曲贝替丁（Trabectedin）对MLPS有效的不寻常机制，指出了嵌合体在诱导导致MLPS发病机制的分化阻滞中的作用。此外，这些发现还暗示了体内获得耐药性的潜在机制。

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

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.