血清细胞外囊泡蛋白质组学分析确定乳腺癌的诊断特征和治疗靶点

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-10-01 DOI:10.1158/0008-5472.CAN-23-3998
Ganfei Xu, Rui Huang, Reziya Wumaier, Jiacheng Lyu, Minjing Huang, Yaya Zhang, Qingjian Chen, Wenting Liu, Mengyu Tao, Junjian Li, Zhonghua Tao, Bo Yu, Erxiang Xu, Lingfeng Wang, Guoying Yu, Olivier Gires, Lei Zhou, Wei Zhu, Chen Ding, Hongxia Wang
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引用次数: 0

摘要

细胞外囊泡(EVs)分析是一种很有前景的非侵入性液体活检方法,可用于乳腺癌(BC)的检测、预后判断和治疗监测。要实现这一策略的潜力,需要全面了解人体样本中 BC 特异性 EVs 的特征和蛋白质组组成。在这项研究中,我们采用了一种基于质谱的数据独立获取(DIA)蛋白质组学方法,对发现队列中来自BC患者(126人)和健康供体(70人)的人类血清EVs进行了表征,并在五个独立队列中验证了这些发现。对EV蛋白质组的研究有助于构建特定的EV蛋白质分类器,用于诊断BC和区分转移性疾病患者。值得注意的是,TALDO1被发现是BC远处转移的EV生物标记物。体外和体内分析证实了TALDO1在刺激BC侵袭和转移中的作用。最后,通过对由271,380个小分子组成的文库进行高通量分子对接和虚拟筛选,发现了一种有效的TALDO1异构抑制剂AO-022,它可以抑制BC在体外的迁移和体内的肿瘤进展。总之,这项工作阐明了BC患者血清EV中的蛋白质组变化,为改进诊断、监测和治疗策略的开发提供了指导。
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Proteomic Profiling of Serum Extracellular Vesicles Identifies Diagnostic Signatures and Therapeutic Targets in Breast Cancer.

Analysis of extracellular vesicles (EV) is a promising noninvasive liquid biopsy approach for breast cancer detection, prognosis, and therapeutic monitoring. A comprehensive understanding of the characteristics and proteomic composition of breast cancer-specific EVs from human samples is required to realize the potential of this strategy. In this study, we applied a mass spectrometry-based, data-independent acquisition proteomic approach to characterize human serum EVs derived from patients with breast cancer (n = 126) and healthy donors (n = 70) in a discovery cohort and validated the findings in five independent cohorts. Examination of the EV proteomes enabled the construction of specific EV protein classifiers for diagnosing breast cancer and distinguishing patients with metastatic disease. Of note, TALDO1 was found to be an EV biomarker of distant metastasis of breast cancer. In vitro and in vivo analysis confirmed the role of TALDO1 in stimulating breast cancer invasion and metastasis. Finally, high-throughput molecular docking and virtual screening of a library consisting of 271,380 small molecules identified a potent TALDO1 allosteric inhibitor, AO-022, which could inhibit breast cancer migration in vitro and tumor progression in vivo. Together, this work elucidates the proteomic alterations in the serum EVs of breast cancer patients to guide the development of improved diagnosis, monitoring, and treatment strategies. Significance: Characterization of the proteomic composition of circulating extracellar vesicles in breast cancer patients identifies signatures for diagnosing primary and metastatic tumors and reveals tumor-promoting cargo that can be targeted to improve outcomes.

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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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