Prognostic Metabolic Signatures of Cancers Through Mass Spectrometry Imaging

描述（由申请人提供）：肿瘤发生的一个标志性特征是代谢的全球变化。容易地测量原位代谢的能力可以为癌症的早期检测提供强有力的策略，以及基于与特定癌基因表达相关的某些代谢特征的检测来更好地诊断和预测癌症的能力，并且最终可以发现可以作为更好的治疗靶点的癌症的新分子基础。MYC癌基因是人类肿瘤发生的最常见的相关原因之一，特别是与造血肿瘤（包括淋巴瘤和上皮肿瘤如肝细胞癌）的发病机制相关。MYC通过作为涉及许多细胞程序的转录的全局调节剂起作用而促进肿瘤发生，特别是与瓦尔堡效应相关的细胞增殖、生长和代谢。MYC调节糖酵解、β-氨基分解、三羧酸循环、C1/叶酸、嘌呤、嘧啶和特别是脂质代谢中的关键基因。这表明特定代谢特征的原位分析可能是检测、诊断和预测MYC相关人类肿瘤的非常有用的方法。然而，使用现有的方法，还不容易进行代谢的原位分析。现在，我们已经开发出一种高度敏感的方法，使我们能够使用一种创新形式的质谱法来提供MYC诱导的癌症代谢的显微镜检查。这种分析的一个关键特征是能够提供基本上实时的原位分析。这种方法被称为解吸电喷雾电离质谱成像（ESI-MSI），用含有乙腈和二甲基甲酰胺的微滴轰击细胞和/或组织切片，这些微滴溶解了数百种脂质和代谢物。在这个提议中，我们将使用MSI作为一种工具，用于识别与淋巴瘤中MYC表达有因果关系的代谢特征。我们将使用这种方法来破译MYC通过所鉴定的代谢物产生癌症的生物学机制。

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.