Metabolism supplies the bioenergetic and biosynthetic pathways which underlie all cellular functions. Therefore, to match the metabolic demands of different physiological and pathological states, cells must tightly control nutrient uptake and usage. For instance, quiescent cells import sufficient bioenergetic substrates to sustain homeostasis, but proliferating cells increase nutrient uptake to engage in biosynthesis and duplicate their mass. Due to the poor vascularization of solid tumors, cancer cells exploit alternative nutrient sources to thrive in harsh tumor microenvironments.
Our lab investigates fundamental principles of metabolic regulation in mammalian cells and their co-option in cancer. To understand how cells acquire nutrients, we characterize their cellular import pathways. Here, we are especially interested in metabolic roles of endocytosis and the lysosome. To understand how cells make choices between different nutrient acquisition strategies, we study the regulation of these processes by signal transduction. Here, we focus on the mTORC1 and Ras signaling pathways, which transduce inputs from nutrients and growth factors, respectively. Dysregulated nutrient uptake and metabolism has emerged as a hallmark of cancer. We investigate how cancer cells gain metabolic autonomy to support uncontrolled growth, and promote metabolic flexibility to navigate nutrient-poor tumor microenvironments. We address these questions from multiple angles using a range of cell biological and biochemical techniques, including live imaging, proteomics and metabolite tracing. To discover new metabolic regulators, we conduct genome-wide CRISPR screens in pathophysiologically relevant metabolic environments in cell culture and in mouse models.
We aim to understand how acquisition and metabolism of nutrients is regulated to support cellular function in physiology and carcinogenesis. Studying how oncogenes dysregulate metabolism will substantially contribute to the understanding of cancer biology and identify metabolic vulnerabilities that represent novel targets for cancer therapy. At the same time, this research will uncover how the signaling pathways that become dysregulated in cancer control metabolism during physiological cell growth and stress adaptation.
