Vander Heiden Laboratory

The Vander Heiden Lab is interested in understanding the biochemical pathways cells use to meet the metabolic requirements of cell proliferation, and how regulation of these pathways contributes to cancer biology in vivo. Ultimately, we aim to translate our understanding of cancer cell metabolism into novel cancer therapies.

Cell proliferation requires the conversion of nutrients into biomass. One of the first differences noted between cancer cells and normal cells was a difference in metabolism. We hypothesize that this metabolic difference provides insight into in how proliferating cells, including cancer cells, convert nutrients into the chemical components needed to proliferate. Our laboratory is interested in understanding the biochemical pathways cells use to meet these metabolic requirements of cell proliferation. In addition, we use mouse models of cancer to translate this biochemical understanding of cancer metabolism into better cancer therapies.

A portion of the lab studies the M2 isoform of the glycolytic enzyme pyruvate kinase (PK-M2), which is expressed during embryonic development and in cancer cells. All appear to rely exclusively on PK-M2 as their only pyruvate kinase isoform, while most normal adult tissues express another isoform of pyruvate kinase. PK-M2 is important for aerobic glycolysis, a process involving the conversion of glucose into lactate even when oxygen is abundant. In addition to promoting aerobic glycolysis, PK-M2 is the pyruvate kinase isoform selected during tumor formation in vivo. PK-M2 is different from other pyruvate kinase isoforms because it can bind to proteins that are phosphorylated on tyrosine residues in response to cell growth signals. Phosphotyrosine binding negatively regulates enzymatic activity providing a link between cell growth signals and regulation of glycolysis.

Our findings with PKM2 suggest that less active pyruvate kinase activity may promote aerobic glycolysis and rapid cell proliferation. Thus, a portion of the lab is exploring how cells metabolize glucose when pyruvate kinase activity is low. We are also exploring how enzymes in pathways whose importance was suggested by the metabolic implications of pyruvate kinase activity might regulate metabolism in cancer cells and contribute to tumor growth. We think the biochemical approaches on this project will expand our understanding of pathway biochemistry of proliferating cells.

For another project, we have constructed mouse models to control the expression of pyruvate kinase isoforms, and thus the way in which glucose is metabolized in vivo. These models have been crossed to various mouse models of cancer to understand how metabolic changes contribute to tumorigenesis and tumor maintenance. We are combining these efforts with novel techniques to image metabolism in vivo, and are using small molecules that target enzymes important for cancer metabolism to explore novel therapeutic approaches to target tumor cell metabolism for cancer therapy.

With this research effort, we aim to test the hypothesis that metabolism in cancer is reprogrammed to support the distinct energetic needs of proliferating cells. Unlike normal cells, which rely heavily on ATP to support housekeeping functions, proliferating cells have the additional requirement of duplicating mass. This large synthesis requirement for lipids, amino acids, and nucleotides requires an excess of carbon and reducing equivalents. Metabolic processes in proliferating cells must be reprogrammed to balance ATP production with the production of building blocks required for growth. Ultimately, we hope to acquire a complete accounting of what is required to build a new cells and how metabolic pathways are regulated to facilitate cell proliferation.