Dataset Information

Phosphoproteins in extracellular vehicles as candidate markers for breast cancer

ABSTRACT: The state of protein phosphorylation can be a key determinant of cellular physiology such as early stage cancer, but the development of phosphoproteins from biofluids for disease diagnosis remains elusive. Here we demonstrate, for the first time, a strategy to isolate and identify phosphoproteins in extracellular vehicles from human plasma as potential markers to differentiate disease from healthy states. We identified close to 10,000 unique phosphopeptides, representing 2108 phosphoproteins, in EVs isolated from small volume of plasma samples. Using label-free quantitative proteomics, we quantified 144 phosphoproteins in plasma EVs that are significantly higher in patients diagnosed with breast cancer than in healthy controls. Multiple novel biomarkers were validated in 13 patients using Paralleled Reaction Monitoring and antibody- and non-antibody based assays. The study demonstrated that the development of phosphoproteins in plasma EV as disease biomarkers is highly feasible and may transform cancer screening and monitoring.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: I-Hsuan Chen

LAB HEAD: Weiguo Andy Tao

PROVIDER: PXD005214 | Pride | 2017-03-23

REPOSITORIES: Pride

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Publications

Phosphoproteins in extracellular vesicles as candidate markers for breast cancer.

Chen I-Hsuan IH Xue Liang L Hsu Chuan-Chih CC Paez Juan Sebastian Paez JS Pan Li L Andaluz Hillary H Wendt Michael K MK Iliuk Anton B AB Zhu Jian-Kang JK Tao W Andy WA

Proceedings of the National Academy of Sciences of the United States of America 20170307 12

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. U ...[more]

PMID: 28270605

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Project description:Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factor for AD is the apolipoprotein E4 (E4) allele. APOE4 genotype has been shown to negatively impact on perivascular amyloid clearance, however, its direct influence along with the other APOE variants (APOE2 and APOE3) on the molecular integrity of the cerebrovasculature has not been largely explored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains on different APOE genotype backgrounds. We first interrogated changes between healthy control homozygote E2/E2, E3/E3 and E4/E4 cases to identify underlying genotype specific effects on cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. EIF2, nitric oxide and sirtuin signaling pathways were the top significantly altered pathways in E4/E4 compared to E2/E2 cases. We used a Two-way ANOVA analysis to identify AD-dependent changes and their interactions with APOE genotype. The highest number of significantly regulated proteins from this interaction was observed in E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E4/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E3/E4 cases. These proteomic changes provide novel insights to explain the longstanding link between APOE4 and cerebrovascular dysfunction. The early and converging APOE4 dependent changes we identified could provide novel targets in the cerebrovasculature for developing disease modifying strategies to mitigate the effects of APOE4 genotype on increasing the risk for, and the path towards AD pathogenesis.

Dataset Information

Phosphoproteins in extracellular vehicles as candidate markers for breast cancer

Publications

Phosphoproteins in extracellular vesicles as candidate markers for breast cancer.

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