Yen Ying-Tzu, Zhao Chen, Gao Tian, Yang Jacqueline Ziqian, Kang Ning, Pu Jiahui, Qiu Lei, Hu Qixin, Kim Hyoyong, Wang Anmin, Lee Junseok, Zhang Ryan Y, Liu Na, Ma Yue, Ji You-Ren, Ju Yong, Zheng Lynn L, Lee-South James, Zuo Vivian X, Qian Audrey, Kwan Aaron, Zhang Yating, Zhang Shenghua, Wang Zhili, Ren Jing, Liu Huaichao, Wang Zihan, Yue Yang, Kim Jina, Sun Jennifer, DiBernardo Gabriella A, James-Allan Laura B, Chen Ying, Zhu Weipei, Wang Guoyun, Pei Renjun, Memarzadeh Sanaz, You Sungyong, Rimel Bobbie J, Lawrenson Kate, Karlan Beth Y, Sim Myung Shin, Lu Shaohua, Wan Jipeng, Sun Na, Tseng Hsian-Rong, Zhu Yazhen
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA; California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA; California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA; Cancer Centre, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
EBioMedicine. 2025 Aug 12;119:105884. doi: 10.1016/j.ebiom.2025.105884.
BACKGROUND: Early detection of epithelial ovarian cancer (EOC) is crucial for improving clinical outcomes. However, the sensitivity of primary serological marker cancer antigen 125 (CA125) is suboptimal for detecting early-stage EOC. Tumour-derived extracellular vesicles (EVs) are promising biomarkers for early cancer detection. METHODS: We developed an EOC EV Surface Protein-mRNA Integration (SPRI) Assay for early detection of EOC. This assay quantifies reference mRNAs within subpopulations of EOC EVs enriched by EV Click Beads targeting three EOC EV surface protein markers. Three EOC EV surface protein markers (i.e., FRα, MSLN, and TROP2) were selected through a bioinformatic framework using multi-omics data and underwent rigorous validation using EOC cell lines and EOC tissue microarrays. We then explored the translational potential of the EOC EV SPRI Assay through a phase II case-control study. The EOC EV SPRI Score was established using a logistic regression model in a training cohort (n = 118) and then validated in an independent validation cohort (n = 118). FINDINGS: EOC EV SPRI Score demonstrated superior performance for distinguishing EOC from benign ovarian masses and healthy donors with an area under the receiver operating characteristic (AUROC) of 0.99 (95% CI: 0.97-1.00) in the training cohort and 0.93 (95% CI: 0.88-0.97) in the validation cohort. It outperformed matched serum CA125, and the performance remained excellent in earlier stages of EOC (Stage I/II, AUROC = 0.93, 95% CI: 0.88-0.98) and the subgroup of high-grade serous carcinoma (AUROC = 0.97, 95% CI: 0.87-0.97). INTERPRETATION: The EOC EV SPRI assay demonstrated significant potential for early detection of EOC and improving long-term patient outcomes. FUNDING: This work is supported by National Institutes of Health (R01CA277530, R01CA255727, R01CA253651, R01CA253651-04S1, R21CA280444, R01CA246304, U01EB026421, R44CA288163, U01CA271887, and U01CA230705), DOD (HT9425-23-1-0361) and OCRA (CRDG-2023-3-1000) for the U.S. STUDY: Additionally, we acknowledge the support of the Science and Technology Foundation of Suzhou (SZS2023006, SSD2023004) and the Youth Innovation Promotion Association CAS (2023335) for the work conducted at SINANO.
背景：上皮性卵巢癌（EOC）的早期检测对于改善临床结局至关重要。然而，原发性血清学标志物癌抗原125（CA125）在检测早期EOC时敏感性欠佳。肿瘤来源的细胞外囊泡（EVs）是早期癌症检测中很有前景的生物标志物。 方法：我们开发了一种用于EOC早期检测的EOC EV表面蛋白-mRNA整合（SPRI）检测法。该检测法对通过靶向三种EOC EV表面蛋白标志物的EV点击磁珠富集的EOC EV亚群中的参考mRNA进行定量。通过使用多组学数据的生物信息学框架选择了三种EOC EV表面蛋白标志物（即FRα、MSLN和TROP2），并使用EOC细胞系和EOC组织微阵列进行了严格验证。然后，我们通过一项II期病例对照研究探索了EOC EV SPRI检测法的转化潜力。EOC EV SPRI评分通过逻辑回归模型在一个训练队列（n = 118）中建立，然后在一个独立的验证队列（n = 118）中进行验证。 结果：在训练队列中，EOC EV SPRI评分在区分EOC与良性卵巢肿块及健康供体方面表现出色，受试者操作特征曲线下面积（AUROC）为0.99（95%CI：0.97 - 1.00），在验证队列中为0.93（95%CI：0.88 - 0.97）。它优于匹配的血清CA125，并且在EOC的早期阶段（I/II期，AUROC = 0.93，95%CI：0.88 - 0.98）和高级别浆液性癌亚组（AUROC = 0.97，95%CI：0.87 - 0.97）中表现仍然出色。 解读：EOC EV SPRI检测法在EOC的早期检测及改善患者长期结局方面显示出巨大潜力。 资助：这项工作得到了美国国立卫生研究院（R01CA277530、R01CA255727、R01CA253651、R01CA253651 - 04S1、R21CA280444、R01CA246304、U01EB026421、R44CA288163、U01CA271887和U01CA230705）、美国国防部（HT9425 - 23 - 1 - 0361）和卵巢癌研究联盟（CRDG - 2023 - 3 - 1000）的支持。 研究：此外，我们感谢苏州科技基金（SZS2023006、SSD2023004）和中国科学院青年创新促进会（2023335）对在苏州纳米所开展的工作的支持。
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