Using the secondary structure (beta-sheet) of exosomal proteins for noninvasive pancreatic cancer detection

利用外泌体蛋白的二级结构（β-折叠）进行非侵入性胰腺癌检测

• 批准号: 10046870
• 负责人: Dali Sun
• 金额: $ 14.5万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046870
• 关键词: Biogenesis; Bioinformatics; Biological Assay; Biological Markers; Blood Circulation; Breast; Cancer Detection; Cancer Etiology; Cells; Cessation of life; Circular Dichroism; Circular Dichroism Spectroscopy; Clinical; Colorectal; DNA; Data; Data Analyses; Data Collection; Death Rate; Detection; Diagnosis; Diagnostic Procedure; Disease; Dyes; Early Diagnosis; Excision; Fluorescence; Immune; Individual; Inferior; Investigation; Malignant Epithelial Cell; Malignant neoplasm of pancreas; Marker Discovery; Methods; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Play; Protein Databases; Proteins; Proteomics; RNA; Risk; Role; Spectrometry; Stains; Structure; Sum; Survival Rate; Testing; Therapeutic; Time; United States; Validation; base; beta pleated sheet; cancer type; candidate marker; cohort; design; exosome; experimental study; high reward; improved; in vivo; insight; mortality; neoplastic cell; noninvasive diagnosis; novel; outcome forecast; pancreatic cancer cells; pre-clinical; simulation; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT With a 5-year survival rate of less than 5%, pancreatic ductal adenocarcinoma (PDAC) as a devastating disease has an inferior prognosis, and prolonged survival is achieved only by resection with macroscopic tumor clearance. Although surgical resection can potentially cure early-stage disease, more than 80% of patients present with locally advanced or metastatic disease at the time of diagnosis and are ineligible for resection. Hence, early detection could significantly reduce mortality and improve prognosis. Exosomes secreted by tumor cells actively participate in tumor progression and metastasis and contain multiple biomolecules reflecting the status of their parental tumor cells. Although the biogenesis is still not clear, exosomes released into circulation are under intensive study mostly for its pivotal clinical potential for non- invasive early detection. Most of these studies focused on exosomal single protein/RNA/DNA, or molecular signatures based on multiplex assays. To date, none of the candidate markers have been validated to be adequate for clinical prognosis or diagnosis, which underlies the problem in current exosomal marker discovery approaches. We studied the collective attribute of exosomes by scrutinizing the secondary structure of the exosomal proteins. Our preliminary data strongly suggest that the tumor cell secretes more β-sheet rich proteins through exosomes than the normal cell. The objective of this proposal is to validate the findings in multiple ways, providing evidence that the secondary structure of the exosomal proteins can be used for cancer detection. Successful data collection and analysis from this low-risk and high-reward study will not only justify that a tumor cell sheds more β-sheet rich proteins through exosomes than a normal cell, but will also uncover an insight into the association between exosomes and pancreatic cancer cell states, thus providing a method that can potentially serve as biomarkers and therapeutic choices for pancreatic cancer.

项目概要/摘要 胰腺导管腺癌 (PDAC) 的 5 年生存率低于 5%，是一种毁灭性的癌症 该病预后较差，只有通过肉眼切除才能延长生存期。 肿瘤清除。尽管手术切除有可能治愈早期疾病，但超过 80% 诊断时患有局部晚期或转移性疾病且不适合接受治疗的患者 切除。因此，早期发现可以显着降低死亡率并改善预后。外泌体 肿瘤细胞分泌的多种物质积极参与肿瘤的进展和转移。 反映其亲代肿瘤细胞状态的生物分子。尽管其生物起源仍不清楚， 释放到循环中的外泌体正在接受深入研究，主要是因为其对非 侵入性早期检测。这些研究大部分集中在外泌体单一蛋白/RNA/DNA，或分子 基于多重分析的签名。迄今为止，还没有任何候选标记被验证为 足以用于临床预后或诊断，这是当前外泌体标记物问题的根源 发现方法。我们通过仔细检查次级来研究外泌体的集体属性 外泌体蛋白质的结构。我们的初步数据强烈表明肿瘤细胞分泌 与正常细胞相比，通过外泌体产生更多富含 β-折叠的蛋白质。该提案的目标是 以多种方式验证研究结果，提供证据表明二级结构 外泌体蛋白可用于癌症检测。由此成功的数据收集和分析 低风险和高回报的研究不仅证明肿瘤细胞会脱落更多富含β-折叠的蛋白质 与正常细胞相比，通过外泌体，但也将揭示之间的关联 外泌体和胰腺癌细胞状态，从而提供了一种可能作为 胰腺癌的生物标志物和治疗选择。