Viruses hijack host cell metabolism to promote increased nutrient uptake and anabolism to meet the bioenergetic and biosynthetic demands of virus replication; changes similar to the enhanced glycolysis and anabolic metabolism widely observed in cancer cells. However, unlike cancer cells, viruses undergo intense selection for efficiency, and rapidly and robustly reprogram host cell metabolism through activation of specific key flux-altering nodes, rather than whole metabolic pathway gene sets. Although the mechanisms leading to enhanced anabolism in cancer are well-studied, the mechanisms used by viruses to hijack host cell metabolism are still largely unknown. In 2014, we reported that adenovirus infection increases host cell anabolic metabolism via MYC activation of specific metabolic target genes, only a subset of those turned on by MYC in many cancers.
How adenovirus-induced MYC activation leads to selective transcription of target genes remains unknown. Additionally, the specific compilation of metabolic genes altered by adenovirus infection is currently undefined. We are now elucidating the mechanistic events necessary for adenovirus-induced metabolic changes and the impact they have on anabolic metabolism and virus replication, with the goal of identifying key enzymes essential for anabolism in cancer cells. Because viruses are so efficient at reprogramming host cell metabolism towards increased anabolism, they represent a powerful tool to identify important metabolic enzymes for anabolic metabolism, and potentially the most promising cancer metabolism drug targets. We are also studying ways by which other viruses, including Zika Virus and SARS-CoV-2, hijack host metabolism to promote optimal virus replication.
Metabolic requirements of malignant cell proliferation
Regulation of metabolic pathways. A major goal of the lab is to understand how cancer cells regulate flux through metabolic pathways in order to meet the biosynthetic requirements for proliferation. We are examining three potential layers of metabolic regulation:
Transcriptional regulation of specific metabolic enzymes is vital for biomass production. Duplicating biomass for cell division requires cancer cells to coordinate the activities of numerous metabolic pathways. The precise contributions of many of these pathways remain to be defined. By correlating gene expression with glycolytic flux in tumors, we have identified potentially critical regulators whose activity may influence biomass production and tumor growth.
Post-transcriptional regulation of metabolic enzymes. While transcriptional regulation alters the levels of many metabolic enzymes in cancer, oncogenic signaling may also alter post-transcriptional regulation of metabolic transcripts as well as post-translational modification of metabolic enzymes.
Subcellular localization of metabolic enzymes. We are interested in the role that subcellular localization of metabolic enzymes plays in regulating flux through key biosynthetic pathways.
Nutrient requirements to promote cell growth. We are investigating nutrient requirements and metabolic plasticity of cancer cells in culture and tumors in vivo. There are minimal biosynthetic requirements for the cell to divide, but how cells achieve these minimal requirements is quite variable and adaptable to nutrient availability. We are using liquid chromatography followed by tandem-mass spectrometry (LC-MS/MS) to monitor nutrient consumption and production by cells under various nutrient stresses. With drugs targeting metabolic pathways entering the clinic, insight into cancer nutrient requirements for growth and metabolic plasticity may advise effective combination treatments.
Metabolic modulation of cell fate determination
Adult tissue stem cells regulate organ homeostasis and repair, and thus are continually deciding whether to remain quiescent, proliferate, or differentiate into mature cell types. These decisions often integrate external cues such as the nutritional status of the organism. From cancer studies we know that nutrients and metabolites involved in epigenetic and signaling pathways can actively modulate cell behavior. However, exactly how metabolism influences tissue stem cell fate decisions is still poorly understood. One reason is that tissue stem cell activity needs to be studied within the context of a specific tissue niche and cannot be fully recapitulated in culture. Furthermore, most mainstream methods cannot characterize the metabolism of small populations of cells within a tissue niche. As a result, little is known about the metabolic changes that drive tissue stem cell activation in vivo, or the degree to which these processes are affected by discrete nutrient levels in the diet.
In order to address these questions we are actively developing new isolation techniques and LC/MS-MS measurement methodologies to characterize tissue stem cell metabolism within the tissue niche, using multiple models including mice and tissue stem cell-derived organoids. We are utilizing these new methods in conjunction with genetic and pharmacologic approaches for metabolic perturbation to dissect the role that metabolism plays in regulating stem cell biology in a wide variety of contexts including nutrient regulation of tissue stem cell fate decisions, tissue stem cell states in the developing fetus, and metabolic cross-talk that directs adult stem cell mediated tissue homeostasis and repair.
