Abstract IA03: 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. Research in cancer metabolism is motivated in part by the hope that understanding the basis of metabolic reprogramming will stimulate the development of new approaches in cancer imaging and therapy, both of which have historically capitalized on the altered metabolic states of tumors. Over the past decade, a large number of mechanisms by which oncogene-directed perturbations of signal transduction regulate intermediary metabolism have been defined. Conversely, it has also become apparent that metabolites themselves influence gene expression and signaling in ways that appear to promote malignancy. However, there is still little agreement as to the breadth of metabolic programs that can support cancer cell survival and growth, and more importantly, about which of the myriad metabolic activities observed in culture are relevant to bona fide tumor metabolism in vivo. I will discuss approaches to address these two challenges. First, I will discuss efforts to link functional metabolic pathway choices with oncogenotypes, gene expression networks and therapeutic sensitivities using a systematic analysis of a large panel of lung cancer cell lines. In these studies, cell-autonomous metabolic phenotypes were scored using a set of quantitative features (nutrient consumption, nutrient addiction, 13C labeling patterns), then cross-referenced against a rich set of orthogonal databases to identify genotype-phenotype connections and novel relationships between metabolism and therapeutic sensitivities. Second, I will describe efforts to probe metabolism in human tumors using methods that report on both cell-autonomous and non-cell autonomous influences. We have developed clinical studies involving a combination of pre-surgical imaging and intra-operative 13C infusions to assess metabolic heterogeneity between individual non-small cell lung cancers in human patients, and to characterize the extent of metabolic heterogeneity within individual tumors. 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. Citation Format: Ralph J. DeBerardinis. Metabolic heterogeneity in cancer cells and tumors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA03.