Characterization of a novel sarcoma cell line with an EWSR1::POU2AF3 fusion.

IF 2.3 4区 医学 Q3 ONCOLOGY
Pathology & Oncology Research Pub Date : 2025-03-11 eCollection Date: 2025-01-01 DOI:10.3389/pore.2025.1611986
Hannah Schwab, Maximilian Kerkhoff, Pauline Plaumann, Stéphane Collaud, Uta Dirksen, Dirk Theegarten, Thomas Herold, Stavros Kalbourtzis, Servet Bölükbas, Balazs Hegedüs, Luca Hegedüs
{"title":"Characterization of a novel sarcoma cell line with an EWSR1::POU2AF3 fusion.","authors":"Hannah Schwab, Maximilian Kerkhoff, Pauline Plaumann, Stéphane Collaud, Uta Dirksen, Dirk Theegarten, Thomas Herold, Stavros Kalbourtzis, Servet Bölükbas, Balazs Hegedüs, Luca Hegedüs","doi":"10.3389/pore.2025.1611986","DOIUrl":null,"url":null,"abstract":"<p><p>Sarcomas with an EWSR1::POU2AF3(COLCA2) fusion are a very recently described entity of preferentially sinonasal origin and with undifferentiated round/spindle cell morphology. We established a novel cell line (PF1095) carrying a EWSR1::POU2AF3 fusion from the malignant pleural effusion of a 25-year-old sarcoma patient. The patient was first diagnosed with poorly differentiated neuroendocrine carcinoma based on tumor cell morphology and positivity to markers such as EMA, synaptophysin, and CD56. Later, the EWSR1 translocation was identified in the tumor cells with unknown partners and the patient received chemotherapy according to the Ewing 2008 protocol in combination with surgery and proton beam radiotherapy. At the time of cell line establishment, the disease progressed to pleural sarcomatosis with pleural effusion. In the cell line, we identified POU2AF3 as a fusion partner of EWSR1 and a TP53 frameshift deletion. Next, we determined the sensitivity of PF1095 cells to the currently approved chemotherapies in comparison to two conventional Ewing sarcoma lines (EW-7 and MHH-ES1) with the two most frequent EWSR::FLI1 fusions. Finally, we tested potential new combination therapies. We performed cell viability, proliferation, and cell cycle assays. We found that the proliferation rate of PF1095 cells was much slower than the EWSR1::FLI1 fusion lines and they also had a lower sensitivity to both irinotecan and doxorubicin treatment. Expression level of SLFN11, a predictor of sensitivity to DNA damaging agents, was also lower in PF1095 cells. Combination treatment with the PARP inhibitors olaparib and irinotecan or doxorubicin synergistically reduced cell viability and induced cell death and cell cycle arrest. This unique cell model provides an opportunity to test therapeutic approaches preclinically for this novel and aggressive sarcoma entity.</p>","PeriodicalId":19981,"journal":{"name":"Pathology & Oncology Research","volume":"31 ","pages":"1611986"},"PeriodicalIF":2.3000,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932835/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pathology & Oncology Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/pore.2025.1611986","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Sarcomas with an EWSR1::POU2AF3(COLCA2) fusion are a very recently described entity of preferentially sinonasal origin and with undifferentiated round/spindle cell morphology. We established a novel cell line (PF1095) carrying a EWSR1::POU2AF3 fusion from the malignant pleural effusion of a 25-year-old sarcoma patient. The patient was first diagnosed with poorly differentiated neuroendocrine carcinoma based on tumor cell morphology and positivity to markers such as EMA, synaptophysin, and CD56. Later, the EWSR1 translocation was identified in the tumor cells with unknown partners and the patient received chemotherapy according to the Ewing 2008 protocol in combination with surgery and proton beam radiotherapy. At the time of cell line establishment, the disease progressed to pleural sarcomatosis with pleural effusion. In the cell line, we identified POU2AF3 as a fusion partner of EWSR1 and a TP53 frameshift deletion. Next, we determined the sensitivity of PF1095 cells to the currently approved chemotherapies in comparison to two conventional Ewing sarcoma lines (EW-7 and MHH-ES1) with the two most frequent EWSR::FLI1 fusions. Finally, we tested potential new combination therapies. We performed cell viability, proliferation, and cell cycle assays. We found that the proliferation rate of PF1095 cells was much slower than the EWSR1::FLI1 fusion lines and they also had a lower sensitivity to both irinotecan and doxorubicin treatment. Expression level of SLFN11, a predictor of sensitivity to DNA damaging agents, was also lower in PF1095 cells. Combination treatment with the PARP inhibitors olaparib and irinotecan or doxorubicin synergistically reduced cell viability and induced cell death and cell cycle arrest. This unique cell model provides an opportunity to test therapeutic approaches preclinically for this novel and aggressive sarcoma entity.

与EWSR1::POU2AF3融合的新型肉瘤细胞系的表征。
伴有EWSR1::POU2AF3(COLCA2)融合的肉瘤是最近才被发现的一种主要起源于鼻窦的肉瘤,具有未分化的圆形/纺锤形细胞形态。我们从一名25岁肉瘤患者的恶性胸腔积液中建立了一株携带EWSR1::POU2AF3融合的新细胞系(PF1095)。根据肿瘤细胞形态和EMA、synaptophysin、CD56等标志物阳性,患者首次被诊断为低分化神经内分泌癌。随后,在伴体未知的肿瘤细胞中发现了EWSR1易位,患者根据Ewing 2008方案接受化疗,联合手术和质子束放疗。在细胞系建立时,病情发展为胸膜肉瘤伴胸膜积液。在细胞系中,我们发现POU2AF3是EWSR1和TP53移码缺失的融合伴侣。接下来,我们确定了PF1095细胞对目前批准的化疗的敏感性,并将其与两种最常见的EWSR::FLI1融合的传统尤文氏肉瘤系(ew7和MHH-ES1)进行比较。最后,我们测试了潜在的新联合疗法。我们进行了细胞活力、增殖和细胞周期测定。我们发现PF1095细胞的增殖速度比EWSR1::FLI1融合系慢得多,而且它们对伊立替康和阿霉素的敏感性都较低。SLFN11在PF1095细胞中的表达水平也较低,SLFN11是对DNA损伤剂敏感性的预测因子。与PARP抑制剂奥拉帕尼和伊立替康或阿霉素联合治疗可协同降低细胞活力,诱导细胞死亡和细胞周期阻滞。这种独特的细胞模型为临床前测试这种新型侵袭性肉瘤实体的治疗方法提供了机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.30
自引率
0.00%
发文量
134
审稿时长
4-8 weeks
期刊介绍: Pathology & Oncology Research (POR) is an interdisciplinary Journal at the interface of pathology and oncology including the preclinical and translational research, diagnostics and therapy. Furthermore, POR is an international forum for the rapid communication of reviews, original research, critical and topical reports with excellence and novelty. Published quarterly, POR is dedicated to keeping scientists informed of developments on the selected biomedical fields bridging the gap between basic research and clinical medicine. It is a special aim for POR to promote pathological and oncological publishing activity of colleagues in the Central and East European region. The journal will be of interest to pathologists, and a broad range of experimental and clinical oncologists, and related experts. POR is supported by an acknowledged international advisory board and the Arányi Fundation for modern pathology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信