Characterization of Gene-Environment Interactions That Govern Metabolic Adaptation

Metabolism is known to be driven by intrinsic genetic programs as well as contextual factors within the environment. Individual genetic and environmental determinants of metabolic state have been extensively characterized, both within normal physiological processes as well as in the context of disease states such as cancer. However, it is becoming increasingly appreciated that the inevitable interaction between these differential sources of metabolic regulation can dramatically influence cellular phenotypes, a phenomenon commonly referred to as gene-environment interaction. These interactions can create substantial heterogeneity between individuals, particularly in the context of tumor metabolism which can ultimately impede the development and efficacy of many clinical therapies. Characterization of these relationships can therefore improve the predictive applicability of targeted therapeutic approaches, as well as contribute to the identification of novel treatment strategies that can circumvent the biological limitations imposed by gene-environment interactions. Using metabolomic, genetic, and pharmacological approaches, in this dissertation I examine the metabolic consequences of environmental alterations in defined genetic settings. I provide in-depth characterization of the relative predictability of cellular responsiveness to nutrient availability in the context of genetic deletion of the metabolic enzyme MTAP, results of which demonstrate potential implications in previously-identified metabolic vulnerabilities in MTAP-deleted cancers. I additionally examine how perturbation of energetic demand, via either pharmacological inhibition of the Na+/K+ ATPase or with the physiological stimulus of exercise, impacts metabolic processes in diverse biological contexts. This work collectively illustrates the exceptional heterogeneity in metabolic adaptation to environmental alterations, and provides support for the future development of lifestyle modifications and repurposing of common pharmacological agents as therapeutic modalities in cancer treatment.