Prognostic Metabolic Signatures of Cancers Through Mass Spectrometry Imaging

通过质谱成像预测癌症的代谢特征

• 批准号: 8673796
• 负责人: DEAN W FELSHER
• 金额: $ 56.96万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673796
• 关键词: Acetonitriles; Analytical Chemistry; Biological; Cell Proliferation; Cells; Chemicals; Chemistry; Citric Acid Cycle; Clinical; Communication; Detection; Diagnosis; Dimethylformamide; Epithelial; Etiology; Folate; Gene Expression; Generations; Genes; Genetic Transcription; Glycerophospholipids; Glycolysis; Growth; Hematopoietic Neoplasms; Human; Human Cell Line; Image; In Situ; In Vitro; Laboratories; Lasso; Lipids; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolism; Methods; Microarray Analysis; Microscopic; Molecular; Mus; Oncogenes; Pathogenesis; Pathway interactions; Phenotype; Pilot Projects; Primary carcinoma of the liver cells; Publishing; Purines; Pyrimidine; Research Personnel; Sampling; Screening for cancer; Specimen; Spectrometry, Mass, Electrospray Ionization; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Universities; Validation; Warburg Effect; base; cancer cell; in vivo; innovation; lipid metabolism; mass spectrometer; medical schools; mouse model; novel; prognostic; programs; public health relevance; purine; statistics; therapeutic target; tool; tumor; tumor metabolism; tumorigenesis

DESCRIPTION (provided by applicant): A hallmark feature of tumorigenesis is the global shift in metabolism. The ability to easily measure metabolism in situ could provide a powerful strategy for the early detection of cancers, as well as the ability to better diagnose and prognosticate cancers based on the detection of certain metabolic signatures related to specific oncogene expression and finally could uncover novel molecular underpinnings of cancer that could serve as better therapeutic targets. The MYC oncogene is one of the most commonly implicated causes of human tumorigenesis, in particular associated with the pathogenesis of hematopoietic tumors including lymphoma and epithelial tumors such as hepatocellular carcinoma. MYC contributes to tumorigenesis by functioning as a global regulator of transcription involving many cellular programs, in particular, cellular proliferation, growth and metabolism associated with the Warburg effect. MYC regulates key genes in glycolysis, glutaminolysis, tricarboxylic acid cycle, C1/folate, purine, pyrimidine and, notably, lipid metabolism. This suggests that in situ analysis of specific metabolic signatures could be a highly useful approach to detect, diagnose and prognosticate MYC-associated human tumors. However, using existing methods, it has not been readily possible to perform an in situ analysis of metabolism. Now, we have developed a highly sensitive approach that will enable us to use an innovative form of mass spectrometry to provide microscopic examination of the MYC-induced cancer metabolism. A key feature of this analysis is the ability to provide essentially rea time, in situ analysis. The method - called Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI) - bombards cells and/or tissue sections with microdroplets containing acetonitrile and dimethylformamide that dissolve hundreds of lipids and metabolites. In this proposal, we will use DESI-MSI as a tool for identifying metabolic signatures causally associated with MYC expression in lymphomas. We will use this approach to decipher the biological mechanism by which MYC generates cancers thought the identified metabolites.

描述（由申请人提供）：肿瘤发生的标志性特征是代谢的全球变化。能够在原位测量新陈代谢的能力可以为癌症的早期检测提供有力的策略，以及基于检测某些与特定癌基因表达相关的某些代谢特征，可以更好地诊断和预测癌症的能力，并最终可以发现新型的癌症分子底钉，这些癌症可以用作更好的治疗目标。 Myc癌基因是人类肿瘤发生的最常见原因之一，尤其是与包括淋巴瘤和上皮肿瘤（如肝细胞癌）的造血肿瘤发病机理有关。 MYC通过充当涉及许多细胞程序的全球转录调节剂，尤其是与Warburg效应相关的细胞增殖，生长和代谢，从而导致肿瘤发生。 MYC调节糖酵解，谷氨酰胺溶解，三羧酸循环，C1/叶酸，嘌呤，嘧啶，嘧啶以及尤其是脂质代谢的关键基因。这表明对特定代谢特征的原位分析可能是一种非常有用的方法来检测，诊断和预测与MYC相关的人类肿瘤。但是，使用现有方法，不容易对代谢进行原位分析。现在，我们已经开发了一种高度敏感的方法，它将使我们能够使用创新的质谱法来提供对MYC诱导的癌症代谢的微观检查。该分析的一个关键特征是能够提供基本上的原位分析时间。该方法称为解吸电喷雾电离质谱成像（DESI -MSI） - 轰击细胞和/或组织切片，这些细胞和/或组织切片含​​有含有乙腈和二甲基甲酰胺的微粒，可溶解数百种脂质和代谢物。在此提案中，我们将使用DESI-MSI作为识别与淋巴瘤中MYC表达相关的代谢特征的工具。我们将使用这种方法来破译MYC产生癌症认为已鉴定的代谢产物的生物学机制。