Tissue stem cells (TSCs) are essential for maintaining and repairing our organs by balancing quiescence, proliferation, and differentiation. Emerging research reveals that metabolism is a key driver of stem cell behavior rather than just a passive byproduct of the cellular environment. Metabolic pathways and specific metabolites influence how TSCs respond to injury, make fate decisions, and interact with their niche. Our research explores how metabolic regulation governs stem cell function in vivo, with a focus on developing new tools and methods to study rare stem cell populations within their native tissue environments. By uncovering these intricate metabolic circuits, we aim to understand how nutrients, diet, and systemic physiology intersect to shape tissue regeneration and stem cell dynamics. Our goal is not only to map the metabolic profiles of tissue stem cells, but to uncover causal relationships between specific metabolic states and stem cell behavior.
Through the implementation of novel tool designs, along with genetic and biochemical perturbations, and functional analyses, we aim to define the mechanistic underpinnings of metabolic regulation in stem cells and contribute to the development of new strategies for regenerative medicine and tissue repair.
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.
Cancer Metabolism
We and others have shown that metabolism regulates cell fate. Cancer is characterized not only by dysregulated cell proliferation, but also by changes in cell state that influence disease progression. We study how metabolism regulates these processes in multiple ways. First, we study tissue- and subtype-specific metabolic dependencies that can be leveraged therapeutically. Second, we study how metabolic changes due to diet or injury in the normal tissue microenvironment can drive tumor initiation.
We also use cancer models to investigate nutrient sensing. By determining how metabolites interact with signaling pathways and transcriptional networks, we aim to uncover novel therapeutic targets that exploit tumor nutrient reliance.
Developmental Metabolism
Cellular metabolism has emerged as a critical regulator of cell fate decisions, but its role in controlling differentiation in vivo during development remains poorly defined. Even less is understood about how maternal metabolic states influence these developmental processes. One pressing motivation for addressing this gap is the growing global incidence of diabetic pregnancy, a condition associated with elevated risks of congenital heart and neurodevelopmental defects. Now affecting up to 10% of U.S. pregnancies, diabetic pregnancy is among the most common complications, according to the CDC.
Despite this, we still do not understand how maternal hyperglycemia leads to developmental anomalies. To begin unraveling this, we are investigating whether and how maternal hyperglycemia perturbs fetal metabolism in utero. In parallel, we aim to determine how metabolic pathways influence normal fetal development in the absence of disease. By dissecting these mechanisms, we hope to uncover the metabolic underpinnings of maternal-fetal interactions during development and establish a framework for understanding how metabolic dysregulation contributes to developmental disorders. To do this, we use a combination of genetic and pharmacological approaches to manipulate fetal metabolism and assess developmental phenotypes.
