Methods to Analyze Tumor Metabolism in Vivo
A major challenge in cancer research is understanding which metabolic pathways operate in live tumors growing in a native microenvironment. Our lab has established clinical protocols combining multiparametric, preoperative imaging with intraoperative infusions of isotope-labeled nutrients (e.g., 13C-glucose) to solve this problem. Our technique allows us to assess metabolic flux in living, human tumors in the lung, brain and other organs and compare fluxes between tumor and adjacent benign tissues. We are also able to correlate metabolic activity with gene expression and histological features. As a result, we have identified numerous metabolic activities that traditional studies confined to cultured cells could not have predicted. We have also adapted our imaging/13C infusion techniques to mouse models of cancer, which allows us to test hypotheses arising from work in human cancer.
Our overall goal is to identify the various fuels that bona fide human tumors consume in vivo and to understand the relative influences of the oncogenotype and stroma on tumor metabolism.
Early results of this work (Hensley et al., Cell 2016) discovered regions of biological heterogeneity have predictable patterns of metabolic heterogeneity. Lung tumors consume a variety of nutrients in vivo, including glucose and a number of alternative fuels such as lactate, fatty acids, and amino acids. Areas of low perfusion as reported by dynamic contrast enhanced MRI have the highest preference for glucose oxidation, and areas of higher perfusion more prominently use alternative fuels (see below). Isotope labeling of tumors and lungs infused with [U-13C]glucose found flux values for enzymes such as pyruvate dehydrogenase and pyruvate carboxylase (PDH and PC) were twice as active in the tumors.
