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      Phosphoproteins in extracellular vesicles as candidate markers for breast cancer

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          Significance

          Protein phosphorylation is a major regulatory mechanism for many cellular functions, but no phosphoprotein in biofluids has been developed for disease diagnosis because of the presence of active phosphatases. This study presents a general 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 from small volumes of plasma samples and more than 100 phosphoproteins in plasma EVs that are significantly higher in patients diagnosed with breast cancer as compared with healthy controls. This study demonstrates that the development of phosphoproteins in plasma EVs as disease biomarkers is highly feasible and may transform cancer screening and monitoring.

          Abstract

          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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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          21 March 2017
          7 March 2017
          : 114
          : 12
          : 3175-3180
          Affiliations
          [1] aDepartment of Biochemistry, Purdue University , West Lafayette, IN 47907;
          [2] bDepartment of Medicinal Chemistry & Molecular Pharmacology, Purdue University , West Lafayette, IN 47907;
          [3] cDepartment of Chemistry, Purdue University , West Lafayette, IN 47907;
          [4] dDepartment of Innovations, Tymora Analytical Operations , West Lafayette, IN 47906;
          [5] eDepartment of Horticulture and Landscape Architecture, Purdue University , West Lafayette, IN 47907;
          [6] fShanghai Center for Plant Stress Biology and Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences , Shanghai 201602, China;
          [7] gPurdue Center for Cancer Research, Purdue University , West Lafayette, IN 47907
          Author notes
          1To whom correspondence may be addressed. Email: jkzhu@ 123456purdue.edu and watao@ 123456purdue.edu .

          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.

          Author information
          http://orcid.org/0000-0001-5134-731X
          Article
          PMC5373352 PMC5373352 5373352 201618088
          10.1073/pnas.1618088114
          5373352
          28270605
          c3c06478-5983-429e-b67f-6437175dca1e
          History
          Page count
          Pages: 6
          Funding
          Funded by: HHS | National Institutes of Health (NIH) 100000002
          Award ID: 5R41GM109626
          Funded by: HHS | National Institutes of Health (NIH) 100000002
          Award ID: 1R01GM111788
          Funded by: HHS | National Institutes of Health (NIH) 100000002
          Award ID: 1R41CA210772
          Funded by: Purdue University 100006377
          Award ID: P30 CA023168
          Funded by: National Science Foundation (NSF) 100000001
          Award ID: 1506752
          Categories
          Biological Sciences
          Medical Sciences

          phosphoproteins,proteomics,extracellular vesicles,mass spectrometry,biomarker

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