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新陈代谢的全球转变。在原位轻松测量代谢的能力可以为癌症的早期检测提供强大的策略，以及基于检测与特定癌基因表达相关的某些代谢特征来更好地诊断和预测癌症的能力，最终可以发现癌症的新分子基础，可以作为更好的治疗靶点。MYC癌基因是人类肿瘤发生最常见的原因之一，特别是与造血肿瘤（包括淋巴瘤）和上皮肿瘤（如肝细胞癌）的发病机制有关。MYC通过作为涉及许多细胞程序的转录的全局调节剂，特别是与Warburg效应相关的细胞增殖、生长和代谢，有助于肿瘤的发生。MYC调节糖酵解、谷氨酰胺解、三羧酸循环、C1/叶酸、嘌呤、嘧啶，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检测、诊断和预测myc相关人类肿瘤的一种非常有用的方法。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的质谱法，对myc诱导的癌症代谢进行显微镜检查。这种分析的一个关键特征是能够提供实时的原位分析。该方法-称为解吸电喷雾电离质谱成像(DESI-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，溶解数百种脂质和代谢物。在本提案中，我们将使用DESI-MSI作为识别与淋巴瘤中MYC表达因果相关的代谢特征的工具。我们将使用这种方法来破译MYC通过已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.