Revealing cancer metabolism via mass spectrometry and isotope tracers

项目总结/文摘

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.