Phosphoproteins in extracellular vesicles as candidate markers for breast cancer

The state of protein phosphorylation can be a key determinant of cellular physiology such as early-stage cancer, but the development of phosphoproteins in biofluids for disease diagnosis remains elusive. Here we demonstrate a strategy to isolate and identify phosphoproteins in extracellular vesicles...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 12; pp. 3175 - 3180
Main Authors Chen, I-Hsuan, Xue, Liang, Hsu, Chuan-Chih, Paez, Juan Sebastian Paez, Pan, Li, Andaluz, Hillary, Wendt, Michael K., Iliuk, Anton B., Zhu, Jian-Kang, Tao, W. Andy
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 21.03.2017
Subjects
Biological Sciences
Biomarkers
Breast cancer
Medical diagnosis
Phosphorylation
Plasma
Proteins
Proteomics
phosphoproteins
mass spectrometry
extracellular vesicles
proteomics
biomarker
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Summary:The state of protein phosphorylation can be a key determinant of cellular physiology such as early-stage cancer, but the development of phosphoproteins in biofluids for disease diagnosis remains elusive. Here we demonstrate a strategy to isolate and identify phosphoproteins in extracellular vesicles (EVs) from human plasma as potential markers to differentiate disease from healthy states. We identified close to 10,000 unique phosphopeptides in EVs isolated from small volumes of plasma samples. Using label-free quantitative phosphoproteomics, we identified 144 phosphoproteins in plasma EVs that are significantly higher in patients diagnosed with breast cancer compared with healthy controls. Several biomarkers were validated in individual patients using paralleled reaction monitoring for targeted quantitation. This study demonstrates that the development of phosphoproteins in plasma EV as disease biomarkers is highly feasible and may transform cancer screening and monitoring.
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Contributed by Jian-Kang Zhu, February 1, 2017 (sent for review November 1, 2016; reviewed by Natalie G. Ahn, Bernd Bodenmiller, and Jim Bruce)
Author contributions: I.-H.C., L.P., A.B.I., J.-K.Z., and W.A.T. designed research; I.-H.C., L.X., C.-C.H., H.A., and A.B.I. performed research; I.-H.C., J.S.P.P., M.K.W., J.-K.Z., and W.A.T. analyzed data; and I.-H.C. and W.A.T. wrote the paper.
Reviewers: N.G.A., University of Colorado; B.B., University of Zurich; and J.B., University of Washington.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1618088114