Proteomic and lipidomic profiling of tumor-derived exosomes for cancer prevention

描述（由申请人提供）： 结肠直肠癌的早期和频繁筛查将使局部早期肿瘤的检测，而他们仍然是可治疗的，从而显着降低与这种疾病相关的急剧死亡率。为了实现这一目标，我们建议采取一种新的方法，将结直肠癌来源的外泌体的脂质组学和蛋白质组学分析相结合，通过提高我们对结直肠癌生物学和细胞间通讯的理解，并通过定义一系列组织特异性标志物来预防结肠癌，这些标志物可用作筛选，分期和随访患者治疗的工具。外泌体是独特的囊泡，其从细胞分泌并从起始位点转运离开以与其局部环境相互作用或通过血液在体内转运。它们独特的蛋白质组谱对肿瘤细胞具有特异性，因此提供了确定组织起源和状态的机会。这些信息可用于改善预防晚期结直肠癌的诊断策略，并进一步了解结直肠癌生物学。首先，我们将定义正常结肠上皮和结直肠癌来源的外泌体的纯化方案。我们将使用新开发的脂质组学方法来定量确定定义肿瘤特异性外泌体的脂质谱。脂质组学分析和蛋白质组学分析与组织特异性蛋白质的叠加的组合将提供一组标志物，其将唯一地鉴定存在于许多体液中的组织特异性肿瘤来源的外泌体。这种将定量外泌体脂质谱与蛋白质谱相结合的独特方法将最终促进我们对结直肠癌生物学中外泌体功能的理解，并能够识别高度信息化和临床有用的生物标志物。

DESCRIPTION (provided by applicant): Early and frequent screening for colorectal cancer will enable detection of localized early-stage tumors while they are still treatable, thus significantly reducing the drastic mortality rate associated with this disease. To achieve this, we propose to take the novel approach of combining lipidomic and proteomic analysis of colorectal cancer-derived exosomes in an effort to prevent colon cancer by improving our understanding of colorectal cancer biology and cell-cell communication and by defining a catalogue of tissue-specific markers that can be used as tools to screen, stage, and follow the treatment of patients. Exosomes are unique encapsulated vesicles that are secreted from cells and transported away from the originating site to interact with their localized environment or transported around the body through blood. Their unique proteomic profiles are specific to the tumor cell and thus provide an opportunity to define tissue origin and status. This information can be used to improve diagnostic strategies for the prevention of late stage colorectal cancer and to gain further insight into colorectal cancer biology. First, we will define a purification protocol for normal colon epithelial and colorectal cancer-derived exosomes. We will use newly developed lipidomic approaches to quantitatively determine the lipid profile that defines tumor-specific exosomes. The combination of lipidomic analysis and proteomic analysis, with an overlay of tissue-specific proteins will provide a set of markers that will uniquely identify tissue-specific tumor-derived exosomes that are present in many body fluids. This unique approach of integrating quantitative exosomal lipid profiles with protein profiles will ultimately advance our understanding of exosome function in colorectal cancer biology and enable the identification of highly informative and clinically useful biomarkers.