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
Michela Pasello, Maria Antonella Laginestra, Maria Cristina Manara, Lorena Landuzzi, Francesca Ruzzi, Margherita Maioli, Evelin Pellegrini, Alessandra De Feo, Pier-Luigi Lollini, Katia Scotlandi
{"title":"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","authors":"Michela Pasello, Maria Antonella Laginestra, Maria Cristina Manara, Lorena Landuzzi, Francesca Ruzzi, Margherita Maioli, Evelin Pellegrini, Alessandra De Feo, Pier-Luigi Lollini, Katia Scotlandi","doi":"10.1002/ccs3.12047","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":15226,"journal":{"name":"Journal of Cell Communication and Signaling","volume":"18 3","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccs3.12047","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ccs3.12047","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.