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

项目摘要/摘要 胰腺导管腺癌(PDAC)的5年生存率不到5%，是一种毁灭性的 疾病预后较差，只有通过宏观切除才能延长生存时间。 肿瘤清除。尽管手术切除有可能治愈早期疾病，但超过80%的 确诊时患有局部晚期或转移性疾病的患者，不符合 切除手术。因此，早期发现可以显著降低死亡率和改善预后。外切体 肿瘤细胞分泌的物质积极参与肿瘤的进展和转移，并含有多种 反映其亲代肿瘤细胞状态的生物分子。虽然其生物发生机制仍不清楚， 释放到循环中的外切体正在进行深入的研究，主要是因为它对非传染性疾病具有关键的临床潜力。 侵入性早期检测。这些研究大多集中在胞外体单一蛋白/RNA/DNA，或分子 基于多重分析的签名。到目前为止，没有一个候选标记被验证为 对于临床预后或诊断是足够的，这是当前胞外标记存在的问题所在 发现号即将到来。我们通过仔细研究次级外切体来研究外切体的集体属性 胞外体蛋白的结构。我们的初步数据有力地表明，肿瘤细胞分泌 与正常细胞相比，更多的富含β-Sheet的蛋白质通过外切体。这项提议的目标是 以多种方式验证这些发现，提供证据表明 胞外体蛋白可用于癌症检测。成功地从中收集和分析数据 低风险和高回报的研究将不仅证明肿瘤细胞释放更多富含β-Sheet的蛋白质 通过外切体比正常细胞，还将揭示两者之间的关联 Exosome与胰腺癌细胞状态之间的关系，从而提供了一种潜在的 胰腺癌的生物标志物和治疗选择。

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.