Associate Professor of Biology
Associate Director, Koch Institute for Integrative Cancer Research
"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."
Mathew Vander Heiden is an associate professor in Department of Biology, an associate director of the Koch Institute at MIT and a member of the Broad Institute. He is a practicing oncologist and instructor in medicine at Dana-Farber Cancer Institute/ Harvard Medical School. He earned his doctoral and medical degrees from the University of Chicago, where he worked in the laboratory of Craig Thompson. Vander Heiden then completed a residency in internal medicine at Boston’s Brigham & Women’s Hospital and a hematology-oncology fellowship at Dana-Farber Cancer Institute / Massachusetts General Hospital. He was a post-doctoral fellow in the laboratory of Lewis Cantley at Harvard Medical School, where he was supported by a Mel Karmazin Fellowship from the Damon Runyon Cancer Research Foundation. In 2010, Vander Heiden joined the MIT faculty. His work has been recognized by many awards including the Burroughs Wellcome Fund Career Award for Medical Sciences, the AACR Gertrude B. Elion Award, the HHMI Faculty Scholar Award, and the Stand Up To Cancer Phillip A. Sharp Innovation in Collaboration Award.
Complex regulatory mechanisms enable metabolism to match cell demands, which extend beyond the production of ATP. To proliferate, cells must transform available nutrients into the varied array of macromolecules that are needed to build a new cell. Despite extensive knowledge about metabolic pathways, and the recognition that metabolism changes are a universal feature of cancer, fundamental questions remain with respect to how different cancers repurpose metabolism to acquire the materials needed for tumor growth. Understanding which products of metabolism are limiting for proliferation, and how cancer cells obtain them in physiological tissue environments, is crucial to exploit metabolism for therapy. The long-term goal of the Vander Heiden laboratory is to understand how mammalian cell metabolism supports cell physiology in normal and disease states with a near-term focus on how metabolism supports cancer cell proliferation.
The metabolic phenotypes of proliferating cells are typically interpreted with an emphasis on either energy generation or how signaling events affect cell metabolism. This has led many to focus on how cancer genetics influences metabolic pathway use. The Vander Heiden lab takes a different approach that identifies limiting metabolic processes, considers how these are constrained by the extracellular environment, and defines how metabolic limitations are overcome within a physiological tissue context. Using mass spectrometry to trace nutrient fate in systems with altered metabolic regulation, and manipulating culture conditions to understand the effect of environment on metabolism, they generate hypotheses for how cells acquire key biomass components to support proliferation. They leverage our knowledge of metabolism to test these hypotheses using cell culture systems and mouse models. Coupling these approaches with biochemical assays and metabolite measurements, the Vander Heiden group aims to define how nutrient availability, metabolic pathway regulation, and tissue context constrain how cells use available materials to proliferate.
The current interests of the Vander Heiden lab include identifying which products of metabolism create bottlenecks for cell proliferation and understanding how different cancers repurpose metabolism to enable tumor growth. They are also interested in how diet and whole body metabolism influence cell metabolism in tissues to modify cancer and other disease phenotypes. Through their work, they aim to advance understanding of metabolic pathway biochemistry and its relationship to cancer and mammalian physiology.
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.
Muir A, Danai LV, Gui DY, Waingarten CY, Lewis CA, Vander Heiden MG. 2017. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. Elife 6:pii: e27713.
Davidson SM, Jonas O, Keibler MA, Hou HW, Luengo A, Mayers JR, Wyckoff J, Del Rosario AM, Whitman M, Chin CR, et al. 2017. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat Med 23: 235–241.
Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, Lau AN, Ji BW, Dixit PD, Hosios AM, et al. 2016. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353: 1161–1165.
Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC, Steinhauser ML, Manalis SR, Vander Heiden MG. 2016. Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells. Dev Cell 36: 540–549.
Gui DY, Sullivan LB, Luengo A, Hosios AM, Bush LN, Gitego N, Davidson SM, Freinkman E, Thomas CJ, Vander Heiden MG. 2016. Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. Cell Metab 24: 716–727.
Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA, Luengo A, Bauer MR, Jha AK, O’Brien JP, Pierce KA, et al. 2016b. Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell Metab 23: 517–528.
Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. 2015. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell 162: 552–563.
Lunt SY, Muralidhar V, Hosios AM, Israelsen WJ, Gui DY, Newhouse L, Ogrodzinski M, Hecht V, Xu K, Acevedo PNM, et al. 2015. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol Cell 57: 95–107.
Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, Yuan C, Bao Y, Townsend MK, Tworoger SS, et al. 2014. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20: 1193–1198.
Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, et al. 2013. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155: 397–409.