Abstract IA07: Metabolic heterogeneity in cancer cells and tumors

Abstract

Abstract Most diseases are accompanied by altered metabolism at the cellular level. In cancer, metabolic reprogramming that is, the regulated alteration of metabolism as a consequence of tumorigenic mutations and other factors is viewed as an essential component of malignant transformation. It is unknown to what extent cell-autonomous vs. non-cell autonomous factors influence metabolic pathway choice. We performed metabolic profiling in a large panel of molecularly annotated non-small cell lung cancer (NSCLC) cell lines grown in standard monolayer culture in order to define the scope of cell-autonomous metabolic variability in this disease and to understand the mechanisms by which metabolic phenotypes are established. We then identified a new pathway that allows cells to tolerate a cell-extrinsic stress: the loss of anchorage dependence. Regardless of the intrinsic metabolic preferences in monolayer culture, NSCLC cells activated an unconventional pathway allowing reducing equivalents to shuttle from the cytosol to the mitochondria to counteract oxidative stress during anchorage loss. Finally, we performed clinical studies involving a combination of pre-surgical imaging and intra-operative 13C infusions to assess metabolic heterogeneity between individual NSCLC tumors in human patients, and to characterize the extent of metabolic heterogeneity within individual tumors. These studies revealed enhanced glycolysis and glucose oxidation in tumors compared to adjacent lung, regardless of driver mutation. Surprisingly, we also found that regional metabolic heterogeneity could be mapped prior to surgery by examining tissue perfusion using contrast MRI, and that glucose’s contribution to central carbon metabolism is inversely proportional to tumor perfusion. Together, these efforts identify a complex but finite set of metabolic phenotypes that support cell growth and may predict therapeutic vulnerabilities. They also underscore the potential for both existing and novel imaging approaches to inform about metabolic phenotypes in vivo, including phenotypes specified by both cell-intrinsic and cell-extrinsic factors. Citation Format: Ralph J. DeBerardinis. Metabolic heterogeneity in cancer cells and tumors. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA07.