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; Yazhen Zhu

doi:10.1038/s41467-020-18311-0

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 SadeghiRichard 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, Yazhen Zhu

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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%).

Original language	English (US)
Article number	4489
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18311-0
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-020-18311-0

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Sun, N., Lee, Y. T., Zhang, R. Y., Kao, R., Teng, P. C., Yang, Y., Yang, P., Wang, J. J., Smalley, M., Chen, P. J., Kim, M., Chou, S. J., Bao, L., Wang, J., Zhang, X., Qi, D., Palomique, J., Nissen, N., Han, S. H. B., ... Zhu, Y. (2020). Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring. Nature Communications, 11(1), [4489]. https://doi.org/10.1038/s41467-020-18311-0

Sun, N, Lee, YT, Zhang, RY, Kao, R, Teng, PC, Yang, Y, Yang, P, Wang, JJ, Smalley, M, Chen, PJ, Kim, M, Chou, SJ, Bao, L, Wang, J, Zhang, X, Qi, D, Palomique, J, Nissen, N, Han, SHB, Sadeghi, S, Finn, RS, Saab, S, Busuttil, RW, Markovic, D, Elashoff, D, Yu, HH, Li, H, Heaney, AP, Posadas, E, You, S, Yang, JD, Pei, R, Agopian, VG, Tseng, HR & Zhu, Y 2020, 'Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring', Nature Communications, vol. 11, no. 1, 4489. https://doi.org/10.1038/s41467-020-18311-0

@article{38d5cfc4511f4af3bde549ad23cd3c9d,

title = "Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring",

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%).",

author = "Na Sun and Lee, {Yi Te} and Zhang, {Ryan Y.} and Rueihung Kao and Teng, {Pai Chi} and Yingying Yang and Peng Yang and Wang, {Jasmine J.} and Matthew Smalley and Chen, {Pin Jung} and Minhyung Kim and Chou, {Shih Jie} and Lirong Bao and Jing Wang and Xinyue Zhang and Dongping Qi and Juvelyn Palomique and Nicolas Nissen and Han, {Steven Huy B.} and Saeed Sadeghi and Finn, {Richard S.} and Sammy Saab and Busuttil, {Ronald W.} and Daniela Markovic and David Elashoff and Yu, {Hsiao hua} and Huiying Li and Heaney, {Anthony P.} and Edwin Posadas and Sungyong You and Yang, {Ju Dong} and Renjun Pei and Agopian, {Vatche G.} and Tseng, {Hsian Rong} and Yazhen Zhu",

note = "Funding Information: We acknowledge all the patients and healthy donors who participated in this study. This work was supported by National Institutes of Health grants (R21CA240887, R21CA216807, R21CA235340, R01CA218356, U01CA198900, R01CA253651, R01CA246304, and U01EB026421). N.S. gratefully acknowledges financial support from Collaborative Innovation Center of Suzhou Nano Science and Technology. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-18311-0",

language = "English (US)",

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TY - JOUR

T1 - Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring

AU - Sun, Na

AU - Lee, Yi Te

AU - Zhang, Ryan Y.

AU - Kao, Rueihung

AU - Teng, Pai Chi

AU - Yang, Yingying

AU - Yang, Peng

AU - Wang, Jasmine J.

AU - Smalley, Matthew

AU - Chen, Pin Jung

AU - Kim, Minhyung

AU - Chou, Shih Jie

AU - Bao, Lirong

AU - Wang, Jing

AU - Zhang, Xinyue

AU - Qi, Dongping

AU - Palomique, Juvelyn

AU - Nissen, Nicolas

AU - Han, Steven Huy B.

AU - Sadeghi, Saeed

AU - Finn, Richard S.

AU - Saab, Sammy

AU - Busuttil, Ronald W.

AU - Markovic, Daniela

AU - Elashoff, David

AU - Yu, Hsiao hua

AU - Li, Huiying

AU - Heaney, Anthony P.

AU - Posadas, Edwin

AU - You, Sungyong

AU - Yang, Ju Dong

AU - Pei, Renjun

AU - Agopian, Vatche G.

AU - Tseng, Hsian Rong

AU - Zhu, Yazhen

N1 - Funding Information: We acknowledge all the patients and healthy donors who participated in this study. This work was supported by National Institutes of Health grants (R21CA240887, R21CA216807, R21CA235340, R01CA218356, U01CA198900, R01CA253651, R01CA246304, and U01EB026421). N.S. gratefully acknowledges financial support from Collaborative Innovation Center of Suzhou Nano Science and Technology. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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%).

AB - 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%).

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JO - Nat Commun

JF - Nat Commun

SN - 2041-1723

IS - 1

M1 - 4489

ER -

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

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