(4ca) Systems Biology Approaches to Study Metabolism In Tumors and Stem Cells

Metabolism is central to virtually all cellular functions and plays a significant role in the progression of cancer, diabetes, and infectious diseases. While the interconnectivity of most metabolic pathways is generally (though not completely) well-characterized, we have much to learn in terms of how cell signaling and the microenvironment control metabolic processes (and vice versa). Importantly, the binary nature in which we typically study gene regulation cannot be applied to characterize metabolism, and systems level, quantitative analyses of metabolic processes and their regulation are necessary to elucidate disease mechanisms. Flux, or the rate of substrate conversion per cell per unit time, is the ultimate metric describing in vivo metabolic enzyme activity and captures all levels of protein regulation. Recent analytical and computational advances now allow us to estimate intracellular fluxes in a wide variety of organisms using stable isotope-labeled tracers and mass spectrometry (MS).

My thesis research at the University of Wisconsin-Madison involved the directed differentiation and tissue engineering of human embryonic stem (hES) and induced pluripotent stem (iPS) cells, providing me with the experimental skills and background to manipulate and analyze such systems. As a postdoctoral fellow in chemical engineering at MIT I have learned, developed, and applied experimental and computational tools for studying cell metabolism using stable isotope tracers, including 13C metabolic flux analysis (MFA), isotopomer spectral analysis (ISA), and non-targeted fate detection (NTFD). Using these tools we have demonstrated that hypoxia induces tumor cells to almost exclusively employ reductive metabolism of glutamine through IDH1 for lipogenesis. In the prevailing view of metabolism, glucose oxidation is the primary carbon source used for lipid synthesis, and our results now fundamentally alter our mechanistic understanding carbon utilization in mammals. I have also initiated collaborations which explore the role of M2 pyruvate kinase, the HER2 oncogene, and mutant KRAS in reprogramming cellular metabolism. This unique combination of expertise will enable me to characterize the dynamic interplay between cell signaling, metabolism, and stem cell function.