Mammalian cellular metabolism is a dynamic process that consists of thousands of interconnected reactions and regulatory interactions. While the architecture of metabolic networks is defined by the genome, actual metabolic activity (i.e. metabolic flux) through the pathways varies greatly. Dynamic reprogramming of metabolism enables cells to meet metabolic needs associated with specific cellular states and cellular functions (such as supporting proliferation or activating immune function), and adapt to changes in the environment. The overarching goal of our research is to understand how mammalian cellular metabolism is reprogrammed in response to changes in the environment and cellular state, and how activities in key metabolic pathways can in turn affect cell function. To study this, we combine systems biology approaches, especially fluxomics and metabolomics, with computational modeling and biochemical and genetic techniques. The currently focuses of our lab are the following:
Understanding metabolic adaptation in cancer cells in acidic environments.
As a result of insufficient perfusion and high glycolytic activity, the microenvironment of solid tumors is often acidic. Cancer cells exposed to low extracellular pH adapt to this metabolic stress over time, and the adaptation is often associated with increased metastasis potential and chemoresistance. We seek to quantitatively characterize alterations in metabolic activities of cancer cells subject to acute and chronic acidosis, and identify key metabolic pathways that allow survival and proliferation of cancer cells in an acidic environment. By integrating dynamic measurements of metabolic activity with other systematic approaches, and targeted genetic manipulation, we further aim to elucidate regulatory mechanisms that drive the metabolic adaptation. This knowledge will help develop more specific and effective therapeutic strategies to treat cancer, and contribute to a better mechanistic understanding of how cells sense extracellular environment and regulate its metabolism in response.
Investigating metabolic regulation during macrophage polarization.
In response to different environmental cues, macrophages develop a spectra of phenotypes and cellular functions, including pathogen killing, wound healing, and immune regulation. In tumor microenvironment, macrophages of different activation states have distinct impacts on tumor progression. Macrophage polarization is coupled with specific and profound metabolic reprogramming. However, how this metabolism shift is regulated and how specific metabolic states impact macrophage function is poorly understood. We seek to systematically quantify the dynamic reprogramming of cellular metabolism during macrophage polarization and identify unique and required metabolic alterations associated with different activation states. We further seek to understand the mechanisms by which specific metabolic states affect immune function by studying the effect of polarization-associate metabolite dynamics on epigenetic remodeling and transcriptional regulation in macrophages. This study will bring new insights of how metabolism supports specific cellular function and influence cellular state, and also help understand how specific metabolic environments, such as the microenvironment at tumor site, affects the immune function.
- Fan J, Baeza J, Denu JM. (2016) Investigating histone acetylation stoichiometry and turnover rate. Methods Enzymol. 574:125-48.
- Fan J*, Teng X*, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, Rabinowitz JD. (2015) Human Phosphoglycerate Dehydrogenase Produces the Oncometabolite d-2-Hydroxyglutarate. ACS Chem. Biol. 10(2):510-6.
- Fan J, Krautkramer KA, Feldman JL, Denu JM. (2015) Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10(1):95-108
- Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, Djaballah H, Kanai M, Cheng EH, Judkins AR, Pawel B, Baggs J, Cherry S, Rabinowitz JD, Thompson CB. (2014) Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell. 56(2):205-18
- Fan J*, Ye J*, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD. (2014) Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 510(7504):298-302.
- Ye J*, Fan J*, Venneti S, Wan YW, Pawel BR, Zhang J, Finley LW, Lu C, Lindsten T, Cross JR, Qing G, Liu Z, Simon MC, Rabinowitz JD, Thompson CB. (2014) Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4(12):1406-17
- Fan J, Kamphorst JJ, Mathew R, Cheung MK., White E, Shlomi T, Rabinowitz JD. (2013) Simultaneous aerobic glycolysis and glutamine-supported oxidative ATP production in oncogene-driven renal epithelial cells. Mol. Syst. Biol. 9: 712.
- Fan J, Kamphorst JJ, Rabinowitz JD, Shlomi T. (2013) Fatty acid labeling from glutamine in hypoxia can be explained by isotope exchange without net reductive IDH flux. J. Biol. Chem. 288(43):31363-9