CD99 contributes to the EWS::FLI1 transcriptome by specifically affecting FOXM1-targets involved in the G2/M cell cycle phase, thus influencing the Ewing sarcoma genetic landscape

IF 3.6 3区 生物学 Q3 CELL BIOLOGY Journal of Cell Communication and Signaling Pub Date : 2024-08-02 DOI:10.1002/ccs3.12047
Michela Pasello, Maria Antonella Laginestra, Maria Cristina Manara, Lorena Landuzzi, Francesca Ruzzi, Margherita Maioli, Evelin Pellegrini, Alessandra De Feo, Pier-Luigi Lollini, Katia Scotlandi
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Abstract

Ewing sarcoma (EwS), a highly aggressive malignancy affecting children and young adults, is primarily driven by a distinctive oncogenic fusion, the EWSR1-ETS, whose activity is a key source of epigenetic and clinical heterogeneity. CD99 is constantly present in EwS cells, known to modulate the EwS genetic profile and tumor malignancy. However, the relevance of CD99 alone, or in association with EWSR1-ETS chimeras, is poorly understood. We explored the dynamic relationship between CD99 and EWS::FLI1, the main fusion observed in EwS, by means of model systems with inducible expression of either molecule. The transcriptomic dynamics of cells with or without expression of EWS::FLI1 or CD99 were analyzed and correlated with tumor cell growth. The CD99-associated EwS gene profile was found to have commonalities with the profile induced by EWS::FLI1, but also peculiar differences. Both EWS::FLI1 and CD99 are regulated targets of the DREAM complex, but the CD99 expression specifically impacted genes that are the targets of FOXM1 and are involved in the setting of the G2/M phase of the cell cycle. Most CD99-regulated FOXM1-targeted genes were found to correlate with bad prognosis in two public clinical datasets (R2 platform), further supporting the clinical relevance of CD99-mediated regulation of EwS gene expression.

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CD99 通过特异性影响参与 G2/M 细胞周期阶段的 FOXM1 靶点,从而影响尤文肉瘤的基因格局,为 EWS::FLI1 转录组做出了贡献
尤文肉瘤(EwS)是一种影响儿童和年轻人的高度侵袭性恶性肿瘤,主要由一种独特的致癌融合体 EWSR1-ETS 驱动,其活性是表观遗传和临床异质性的关键来源。CD99 持续存在于 EwS 细胞中,已知可调节 EwS 遗传特征和肿瘤恶性程度。然而,人们对 CD99 单独或与 EWSR1-ETS 嵌合体的相关性知之甚少。我们通过诱导表达CD99和EWS::FLI1(EwS中观察到的主要融合体)的模型系统,探索了两者之间的动态关系。我们分析了表达或不表达 EWS::FLI1 或 CD99 的细胞的转录组动态,并将其与肿瘤细胞的生长联系起来。研究发现,CD99相关的EwS基因图谱与EWS::FLI1诱导的基因图谱有共性,但也有特殊的差异。EWS::FLI1和CD99都是蝶恋花复合体的调控靶标,但CD99的表达特别影响到FOXM1的靶标基因,这些基因参与细胞周期G2/M阶段的设置。在两个公开的临床数据集(R2 平台)中,发现大多数 CD99 调控的 FOXM1 靶向基因与不良预后相关,这进一步支持了 CD99 介导的 EwS 基因表达调控的临床相关性。
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来源期刊
CiteScore
6.40
自引率
4.90%
发文量
40
期刊介绍: The Journal of Cell Communication and Signaling provides a forum for fundamental and translational research. In particular, it publishes papers discussing intercellular and intracellular signaling pathways that are particularly important to understand how cells interact with each other and with the surrounding environment, and how cellular behavior contributes to pathological states. JCCS encourages the submission of research manuscripts, timely reviews and short commentaries discussing recent publications, key developments and controversies. Research manuscripts can be published under two different sections : In the Pathology and Translational Research Section (Section Editor Andrew Leask) , manuscripts report original research dealing with celllular aspects of normal and pathological signaling and communication, with a particular interest in translational research. In the Molecular Signaling Section (Section Editor Satoshi Kubota) manuscripts report original signaling research performed at molecular levels with a particular interest in the functions of intracellular and membrane components involved in cell signaling.
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