Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring

Na Sun, Yi-Te Lee, Ryan Y. Zhang, Rueihung Kao, Pai-Chi Teng, Yingying Yang, Peng Yang, Jasmine J. Wang, Matthew Smalley, Pin-Jung Chen, Minhyung Kim, Shih-Jie Chou, Lirong Bao, Jing Wang, Xinyue Zhang, Dongping Qi, Juvelyn Palomique, Nicolas Nissen, Steven-Huy B. Han, Saeed Sadeghi, Richard S. Finn, Sammy Saab, Ronald W. Busuttil, Daniela Markovic, David Elashoff, Hsiao-hua Yu, Huiying Li, Anthony P. Heaney, Edwin Posadas, Sungyong You, Ju Dong Yang, Renjun Pei (), Vatche G. Agopian (), Hsian-Rong Tseng () and Yazhen Zhu ()
Additional contact information
Na Sun: University of California
Yi-Te Lee: University of California
Ryan Y. Zhang: University of California
Rueihung Kao: University of California
Pai-Chi Teng: Cedars-Sinai Medical Center
Yingying Yang: University of California
Peng Yang: University of California
Jasmine J. Wang: Cedars-Sinai Medical Center
Matthew Smalley: University of California
Pin-Jung Chen: University of California
Minhyung Kim: Cedars-Sinai Medical Center
Shih-Jie Chou: University of California
Lirong Bao: University of California
Jing Wang: University of California
Xinyue Zhang: University of California
Dongping Qi: University of California
Juvelyn Palomique: Cedars-Sinai Medical Center
Nicolas Nissen: Cedars-Sinai Medical Center
Steven-Huy B. Han: University of California
Saeed Sadeghi: University of California
Richard S. Finn: University of California
Sammy Saab: University of California
Ronald W. Busuttil: University of California
Daniela Markovic: University of California
David Elashoff: University of California
Hsiao-hua Yu: Academia Sinica
Huiying Li: University of California
Anthony P. Heaney: University of California
Edwin Posadas: Cedars-Sinai Medical Center
Sungyong You: Cedars-Sinai Medical Center
Ju Dong Yang: Cedars-Sinai Medical Center
Renjun Pei: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Vatche G. Agopian: University of California
Hsian-Rong Tseng: University of California
Yazhen Zhu: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).

Date: 2020
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DOI: 10.1038/s41467-020-18311-0

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