Funding
National Key Research and Development Program of China (NKPs)
National Natural Science Foundation of China (NSFC)
Science and Technology Innovation Plan Of Shanghai Science and Technology Commission (上海市科技创新行动计划项目)
Innovation Research Team of High-level Local University in Shanghai
Program of Shanghai Academic Research Leader (Shanghai Academic Research Leader)
Major Projects of Special Development Funds in Zhangjiang National Independent Innovation Demonstration Zone, Shanghai
Shanghai Municipal Science and Technology Major Project
Fudan Original Research Personalized Support Project
ARTICLE ABSTRACT
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.
