Matthew Vander Heiden

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. My laboratory is interested in understanding the biochemical pathways cells use to meet these metabolic requirements of cell proliferation. In addition, we utilize mouse models of cancer to translate our biochemical understanding of cancer metabolism into better cancer therapies.

Recently, there has been a resurgent interest among the scientific community to understand cancer cell metabolism. This has occurred in part because of the growing realization that many of the major oncogenic driver mutations involved in cancer promote nutrient uptake and anabolic metabolism. Our research has focused on the M2 isoform of the glycolytic enzyme pyruvate kinase (PK-M2), which is expressed during embryonic development and at high levels in cancer cells. All tumors and cell lines studied to date express exclusively PK-M2, while normal adult tissues express another isoform of pyruvate kinase. PK-M2 expression is required for aerobic glycolysis. Aerobic glycolysis, also known as the Warburg effect, involves the conversion of glucose into lactate even when oxygen is abundant and is the form of glucose metabolism observed in most cancers. In addition to promoting aerobic glycolysis, PK-M2 appears to be required for human cancer cells to form tumors 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.

Using PK-M2 regulation as a starting point, our laboratory is using biochemical approaches to understand the pathway biochemistry of proliferating cells. Our current efforts have been to test the hypothesis that cell growth signals reprogram metabolism 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. Efforts to understand how metabolism is reprogrammed to facilitate accumulation of biomass have provided us with new insights into the metabolism of cell proliferation.

We have also 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. We are also using small molecules that target enzymes important for cancer metabolism to explore novel therapeutic approaches to target tumor cell metabolism for cancer therapy.

Clower C.V., Chatterjee D., Wang Z., Cantley L.C., Vander Heiden M.G., Krainer A.R. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A 107:1894-1899, (2010).

Jiang J.K., Boxer M.B., Vander Heiden M.G., Shen M., Skoumbourdis A.P., Southall N., Veith H., Leister W., Austin C.P., Park H.W., Inglese J., Cantley L.C., Auld D.S., Thomas C.J. Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett. 20: 3387-93. (2010).

Vander Heiden, M.G., Locasale, L.W., Swanson, K.D., Sharfi, H., Heffron, G.J., Amador-Noguez, D., Christofk, H.R., Wagner, G., Rabinowitz, J.D., Asara, J.M. and Cantley, L.C. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329: 1492-1299 (2010).

Israelsen, W.J., Vander Heiden, M.G. ATP consumption promotes cancer metabolism. Cell 143: 669-671 (2010).

Metallo, C.M., Vander Heiden, M.G. Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev 24: 2717-2722 (2010).

Locasale J.W., Grassian A.R., Melman T., Lyssiotis C.A., Mattaini K.R., Bass, A.J., Heffron G., Metallo C.M., Muranen T., Sharfi, H., Sasaki, A.T., Anastasiou, D., Mullarky, E., Vokes, N.I., Sasaki, M., Beroukhim, R., Stephanopoulos, G., Ligon, A.H., Meyerson, M., Richardson A.L., Chin L., Wagner, G., Asara, J.M., Brugge, J.S., Cantley, L.C., Vander Heiden, M.G. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genetics Jul 31. doi: 10.1038/ng.890 (2011).

Christofk, H.R., Vander Heiden, M.G., Wu, N., Asara, J.M., Cantley, L.C. (2008) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452: 181-186.

Christofk, H.R., Vander Heiden, M.G., Harris, M.H., Ramanathan, A., Gerszten, R.E., Wei, R., Fleming, M.D., Schreiber, S.L., Cantley, L.C. (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: 230-233.

Vander Heiden, M.G., Cantley, L.C., Thompson, C.B. (2009) Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324: 1029-1033.

Dang, L., White, D.W., Gross, S., Bennett, B.D., Bittinger, M.A., Driggers, E.M., Fantin, V.R., Jang, H.G., Jin, S., Keenan, M.C., Marks, K.M., Prins, R.M., Ward, P.S., Yen, K.E., Liau, L.M., Rabinowitz, J.D., Cantley, L.C., Thompson, C.B., Vander Heiden, M.G., and Su, S.M. Cancer-associated IDH-1 mutations produce 2-hydroxyglutarate. Nature. 462(7274):739-44 (2009)

Boxer, M.B., Jiang, J.-K., Vander Heiden, M.G., Shen, M., Skournbourdis, A.P., Southall, N., Veith, H., Leister, W., Austin, C.P., Park, H.W., Inglese, J., Cantley, L.C., Auld, D.S., and Thomas, C.J. Evaluation of Substituted N,N-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. J.Med.Chem. 53(3):1048-55 (2010).