Methods to Analyze Tumor Metabolism in Vivo
A major challenge is understanding which metabolic pathways promote cancer growth and progression in live tumors growing in a native microenvironment. We established clinical protocols combining multiparametric, preoperative imaging with intra-operative infusions of isotope-labeled nutrients (e.g., 13C-glucose) to address this challenge (Hensley et al, Cell 2016, Faubert et al, Nature Protocols 2022). Our approach allows us to assess metabolism in living, human tumors at multiple organ sites and compare isotope labeling features between tumor and adjacent tissues or between primary and metastatic tumors. This has allowed us to identify metabolic activities that could not have been predicted by experiments confined to cultured cells, and to determine which activities correlate with cancer progression and poor outcomes in patients. We have adapted these isotope labeling techniques to mouse models of cancer, allowing us to test hypotheses arising from observations in human cancer.
One discovery arising from this approach is that lactate provides a carbon source for some human tumors (see figure). Lactate, the end product of glycolysis, is traditionally viewed as a metabolic waste of cancer cells, and that its production and elimination from the cell are required to sustain energy production and redox balance. In some human non-small cell lung cancers, however, isotope labeling patterns indicate that lactate is taken up from the blood and provides a fuel for the tricarboxylic acid cycle (Faubert et al., Cell 2017). Interestingly, patients whose tumors display labeling hallmarks of lactate uptake have worse outcomes than patients whose tumors lack these hallmarks. Moving this observation into mouse models, we found that blocking lactate transport by melanoma cells suppresses metastasis, the leading cause of cancer-associated mortality (Tasdogan et al., Nature 2020). Altogether these findings demonstrate that we can use intra-operative isotope tracing in patients to identify unexpected metabolic activities that drive cancer progression.