Eisen and Chang Career Development Professor
Associate Professor of Biology
Ph.D. 2000, University of Chicago
M.D. 2002, University of Chicago
"One of the first differences described between cancer cells and normal cells was a difference in metabolism. Using a combination of biochemistry, molecular biology and mouse models, our laboratory is interested in understanding how metabolism is regulated to influence different stages of tumor biology with a major goal to find novel approaches to treat cancer in the clinic. Cell proliferation requires the conversion of nutrients into biomass. Studies of this metabolic difference provides insight into in how proliferating cells, including cancer cells, convert nutrients into the chemical components needed to proliferate. Understanding how metabolism is regulated to support cell proliferation is a major focus of our lab; however, a large fraction of cells in tumors are not proliferating. These quiescent tumor cells are resistant to most cancer therapies and therefore represent a critically important cell population that is poorly understood. To better understand how these cancer cells adapt metabolism to survive in an inappropriate tissue context, we are also studying the metabolism of tumors in mouse cancer models with a goal of translating our biochemical understanding of cell metabolism into better cancer therapies."
Learn more about the Vander Heiden lab and their efforts to better understand cancer cell metabolism and how small molecules might be used to activate enzymes and restore the normal state of cells by watching this video: "Inside the Lab: Matthew Vander Heiden, M.D., Ph.D."
The Vander Heiden lab's work is profiled as part of the current interactive exhibits in the Koch Institute Public Galleries. Watch a web version of the story here.
Dr. Vander Heiden is the Eisen and Chang Career Development professor and associate professor of biology at MIT and an instructor in medicine at both Harvard Medical School and the Dana-Farber Cancer Institute. He has been a Member of the Scientific Advisory Board at Agios Pharmaceuticals, Inc. since 2008. He received the Burroughs Wellcome Fund Career Award for Medical Scientists in 2009. Dr. Vander Heiden earned his B.S. in Biological Chemistry, M.D. and Ph.D. from the University of Chicago.
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). 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).
Israelsen W.J., Vander Heiden M.G. ATP consumption promotes cancer metabolism. Cell 143:669-71 (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. Cantley, L.C. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329:1492-1299 (2010).
Vander Heiden M.G. Targeting cell metabolism in cancer patients. Sci. Transl. Med. 2:31ed1 (2010).
Vander Heiden, M.G., Christofk, H.R., Schuman, E., Subtelny, A.O., Sharfi, H., Harlow, E.E., Xian, J., Cantley, L.C. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol. 79:1118-1124 (2010).
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).
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)
Locasale, J.W., Cantley, L.C., Vander Heiden, M.G.Cancer's insatiable appetite. Nature Biotech. 27: 916-917 (2009).
Vander Heiden, M.G., Cantley, L.C., Thompson, C.B. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324: 1029-1033 (2009).
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. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: 230-233 (2008).
Christofk, H.R., Vander Heiden, M.G., Wu, N., Asara, J.M., Cantley, L.C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452: 181-186 (2008).