Revealing cancer metabolism via mass spectrometry and isotope tracers

项目总结/摘要 代谢在癌症生长、诊断（如FDG-PET）和治疗（如放射治疗）中起着重要作用。 抗叶酸剂、天冬酰胺酶）。在过去的十年里，对癌症代谢的研究蓬勃发展， 由于认识到癌症中的代谢变化是由癌基因信号传导引发的， 新的测量工具的出现加速了这一进程。这个NCI研究专家奖将研究 癌症代谢使用最重要的现代工具：质谱和同位素示踪剂。工作 与单位主任约书亚拉宾诺维茨和他的实验室，以及来自罗格斯大学的各种合作者一起， 癌症研究所的新泽西和其他领先的机构，我的目标是在未来5年内实现 以下：（1）优化基于LC-MS的代谢组学方法，专注于超灵敏测量 适用于小活检样本和通过非靶向代谢组学鉴定新代谢物。（二） 发展和优化空间代谢组学的成像质谱方法。(3)把这些联合收割机 方法与同位素示踪剂，以确定在体内肿瘤通量。拉宾诺维茨和我有一个 在同位素示踪方法定量代谢通量方面处于领先地位。我们最近开发了 将各种13 C、15 N和2 H示踪剂注入小鼠体内的方案，目的是实现定量 肿瘤代谢流的影响我们正在推动通过质谱成像实现这些测量， 最终达到单细胞分辨率。产生的数据将提供有关代谢的重要见解 癌症和免疫细胞在天然肿瘤微环境中的病理生理学，从而将告知 治疗选择策略和新疗法的开发。

Project Summary/Abstract Metabolism plays a fundamental role in cancer growth, diagnosis (e.g. FDG-PET), and treatment (e.g. antifolates, asparaginase). Over the past decade, research into cancer metabolism has flourished, contextualized by the realization that metabolic changes in cancer are triggered by oncogene signaling and accelerated by the emergence of new measurement tools. This NCI Research Specialist Award will study cancer metabolism using the most important modern tools: mass spectrometry and isotope tracers. Working together with Unit Director Joshua Rabinowitz and his lab, and a diverse set of collaborators from Rutgers Cancer Institute of New Jersey and other leading institutions, I aim over the next 5 years to achieve the following: (1) Optimize LC-MS-based metabolomic methods, focusing on ultrasensitive measurements appropriate for small biopsy samples and on novel metabolite identification via untargeted metabolomics. (2) Develop and optimize the imaging mass spectrometry methods for spatial metabolomics. (3) Combine these methods with isotope tracers to determine fluxes in tumors in vivo. Rabinowitz and I have a long-standing leadership position in isotope tracer methods for quantitating metabolic fluxes. We have recently developed protocols for infusing a wide variety of 13C, 15N, and 2H-tracers into mice, with the goal of enabling quantitation of tumor metabolic flux. We are pushing to enable these measurements also by mass spectrometry imaging, eventually with single cell resolution. Resulting data will provide critical insights into the metabolic pathophysiology of cancer and immune cells in the native tumor microenvironment and will thereby inform treatment selection strategies and the development of novel therapeutics.