Circulating extracellular vesicles protein expression for early prediction of platinum-resistance in high-grade serous ovarian cancer

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-04-10 DOI:10.1038/s41388-025-03382-4

Vincent Wagner, Molly Morton, Kalpana Deepa Priya Dorayappan, Anna Gonzalez, Lianbo Yu, Takahiko Sakaue, Thomas Conrads, G. Larry Maxwell, Casey Cosgrove, Floor Backes, Qi-En Wang, David E. Cohn, David M. O’Malley, Karuppaiyah Selvendiran

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引用次数: 0

Abstract

Platinum resistance in high-grade serous ovarian carcinoma (HGSOC) portends a poor prognosis. Although initial platinum-based chemotherapy response rates are high, 15-20% of patients demonstrate primary resistance to platinum therapy and almost all patients will develop platinum resistance in the recurrent setting. No predictive or diagnostic biomarkers have been utilized specific to platinum resistance. This study aimed to identify candidate biomarkers for platinum resistance in HGSOC using an extracellular vesicle (EV) based approach. We found differentially expressed and distinct EV proteins, namely TMEM205 and CFH, in patients with platinum-resistant (PR) HGSOC compared to those of platinum-sensitive (PS) patients, utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Expression of these EV proteins were validated in patient-derived PR cell lines as well as in clinically relevant mouse models of HGSOC post-platinum therapy. We corroborated these findings using serum samples from patients with PS and PR-HGSOC. Both EV CFH and EV TMEM205 exhibited excellent diagnostic capability for PR as noted by receiver operating characteristic curves with area under the curve values of 0.95 and 0.84, respectively. The high diagnostic performance of TMEM205 and CFH within EVs compared to the relatively poor performance of conventional serum proteins such as Ca125 suggests their robust potential as non-invasive biomarkers for detecting platinum resistance in HGSOC. Furthermore, the ROC curve for the combined biomarker demonstrated excellent diagnostic performance, with an AUC of 0.973, a true positive rate (TPR) of 0.938, and a false positive rate (FPR) of 0.062. Incorporating this multi-protein biomarker panel alongside established biomarkers further enhances diagnostic accuracy. Serum EV CFH and TMEM205 are promising biomarkers for early detection of platinum resistance in HGSOC and may highlight underlying chemoresistance mechanisms, offering potential future therapeutic targets.

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循环细胞外囊泡蛋白表达对高级别浆液性卵巢癌铂耐药的早期预测

高级别浆液性卵巢癌（HGSOC）的铂耐药预示着预后不良。虽然最初的铂类化疗反应率很高，但15-20%的患者对铂类治疗表现出原发性耐药，几乎所有患者在复发时都会出现铂类耐药。目前还没有针对铂耐药的预测性或诊断性生物标志物。本研究旨在利用基于细胞外囊泡（EV）的方法，确定HGSOC中铂耐药的候选生物标志物。利用液相色谱-串联质谱（LC-MS/MS）技术，我们发现铂耐药（PR） HGSOC患者与铂敏感（PS）患者的EV蛋白TMEM205和CFH表达存在差异。这些EV蛋白的表达在患者来源的PR细胞系以及铂治疗后HGSOC的临床相关小鼠模型中得到了验证。我们使用PS和PR-HGSOC患者的血清样本证实了这些发现。EV CFH和EV TMEM205均表现出较好的PR诊断能力，曲线下面积分别为0.95和0.84。与Ca125等传统血清蛋白相对较差的诊断性能相比，TMEM205和CFH在电动汽车中的高诊断性能表明，它们作为检测HGSOC铂耐药的非侵入性生物标志物具有强大的潜力。此外，联合生物标志物的ROC曲线显示出良好的诊断性能，AUC为0.973，真阳性率（TPR）为0.938，假阳性率（FPR）为0.062。将这种多蛋白生物标志物面板与已建立的生物标志物结合，进一步提高了诊断的准确性。血清EV CFH和TMEM205是早期检测HGSOC铂耐药的有希望的生物标志物，可能突出潜在的化疗耐药机制，提供潜在的未来治疗靶点。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.