Hot Topics in Life Sciences
Cancer Cell Metabolism: Unique Features Inform New Therapeutic Opportunities.
Posted August 14, 2015
Cancer cells become lethal when they form large tumors, metastasize, and colonize diverse tissue types. These functions depend on different metabolic pathways from those active in non-transformed cells. Rapidly growing and proliferating cells require constant biosynthesis, in addition to energy in the form of ATP that all cells need for normal functions. The glucose and glutamine that are exclusively catabolized to water and carbon dioxide in quiescent cells are partly diverted to macromolecule production in dividing cells. Cell metabolism has long been a focus of molecular biology; for the cancer field its study represents a return to original lines of inquiry after years of focus on the genetics of cell transformation and the oncogenes involved in signal transduction pathways. At the May 28, 2015, Hot Topics in Life Sciences symposium Cancer Cell Metabolism: Unique Features Inform New Therapeutic Opportunities, the speakers expressed hope that a synthesis of these two approaches will yield progress in cancer research.
Craig B. Thompson of the Memorial Sloan-Kettering Cancer Center reviewed the basics of cell metabolism. After the initial step in glucose metabolism—glycolysis, conversion of glucose to two molecules of pyruvate—mitochondrial oxidative phosphorylation usually proceeds to yield ATP. But even in the presence of oxygen, many cancer cells divert pyruvate to fermentation, producing lactate. This less rewarding mode of ATP production demands a relatively high rate of glycolysis. Otto Warburg described this shift toward "aerobic glycolysis" in cancer cells in 1924. The molecular and genetic basis of the Warburg effect, however, has only recently come to light. Contrary to Warburg's hypothesis that mitochondrial defects necessitate this shift, most cancer cells maintain the ability to execute oxidative phosphorylation and do fully catabolize a small amount of glucose.
Cancer cells are genetically differentiated from normal cells, but it is now clear that the metabolic shifts they exhibit are also partly required for division of normal cells. In a quiescent cell, maximum ATP production yields enough energy for cellular machinery, and at least 50% of free energy is used for ion transport across the membrane. When a cell divides, glycolytic intermediates are diverted from the tricarboxylic acid (TCA/Krebs) cycle to reserve carbon and nitrogen for fatty acid synthesis and for production of nonessential amino acids. DNA replication demands de novo nucleotide synthesis, beyond the supply garnered from recycling pathways in a non-dividing cell. Ribose, serine, and glycine (byproducts of glucose metabolism), as well as glutamine for pyrimidine production, are needed for nucleotide synthesis.
Thompson noted that previously overlooked clues from cell biology research are fundamental to current work to understand the unique metabolism of cancer cells. Harvey Eagle, who is largely credited with establishing a protocol and eponymous growth medium for culturing mammalian cells, did much of his foundational work with the HeLa cell line, derived from a pancreatic tumor. He observed a key feature of proliferating cells' metabolism when he found that these cells need to be cultured in a buffered solution supplemented with glucose and, to his surprise, high levels of the nonessential amino acid glutamine. In an anabolic cell where Kreb's intermediates are diverted to biosynthesis, glutamine metabolism provides a means of anaplerosis. Indeed, some tumors are said to be "glutamine addicted" and cannot survive without exogenous glutamine. The pharmaceutical company Calithera seeks to exploit this property with a new drug, CB-839, that inhibits glutaminase. It is in phase I clinical trials for treating cancer.
Christian Metallo of the University of California, San Diego, has used metabolic tracing to show that the glutamine contribution to lipogenesis shifts in mammalian cells in an oxygen-dependent manner. Cells cultured under hypoxic conditions, which might mimic those experienced by cancer cells in a poorly vascularized tumor, shift to reductive carboxylation of α-ketoglutarate. This glucose and glutamine derivative is also critical in stem cells. Lydia Finley of the Memorial Sloan-Kettering Cancer Center linked α-ketoglutarate levels in embryonic stem cells to the maintenance of demethylation and pluripotency.
Thompson argued that metabolic shifts that define cancer cells are not a secondary consequence of transformation, as has long been thought. The most common genetic mutations that drive cancers are in proto-oncogenes and tumor suppressor genes, which regulate pathways that control cell division. The constitutive activation of the cell cycle and the loss of checkpoints, however, are not enough to drive unmitigated growth; the cell must also undergo metabolic transformation to meet the energetic and synthetic demands of growth. This hypothesis, although perhaps intuitive, has only gained prominence with observations linking metabolic genes to control by signal transduction pathways.
The most commonly mutated gene in cancers is KRAS. The KRAS protein, a GTPase, normally functions as a molecular switch, relaying signals received by receptor tyrosine kinases and other receptors of extracellular signals. Two of its main targets include the MAPK and PI3K signal transduction cascades. But many indirect targets of KRAS are involved in cellular metabolism, including glucose transporters that are positively regulated by the PI3K/Akt pathway. Glutamine-addicted tumors are often characterized by the oncogenic expression of Myc, a transcription factor that promotes the expression of glutamine transporters as well as metabolic enzymes needed for biosynthesis. Constitutively activated KRAS thus primes a cell to undergo aerobic glycolysis by ensuring a steady influx of glucose. Selina Chen-Kiang of the Weill Cornell Medical College showed that therapies targeting the cell cycle indirectly reduce PI3K activation in cancer cells. In collaboration with Pfizer, her research group has tested the Cdk4/6 inhibitor palbociclib in early-phase clinical trials in Mantle cell lymphoma (MCL) patients. Genetic and biochemical analysis of tumors from palbociclib-responsive MCL patients exhibited reduced glucose transporter expression. Palbociclib is currently being tested as a cancer therapy in five separate clinical trials.
Jon Blenis of the Weill Cornell Medical Center identified another common genetic hallmark of cancer linked to metabolism, activated mTORC1 (mTOR Complex 1) signaling. Pathways that activate this complex integrate metabolism by sensing levels of nutrients, such as amino acids leucine and glutamine. The complex then regulates glucose and glutamine metabolism, amino acid production, and lipid biosynthesis. Blenis's group has screened for targets in the pathways to identify combination therapies for mTORC1-activated cancers. One combines the glutamine metabolism inhibitor BAPTES with the HSP90 inhibitor 17-AAG to reduce transformed cells' ability to carry out aerobic glycolysis and confront oxidative stress. A novel downstream target of mTORC1, the kinase SPRK2, is another promising lead.
Each tumor arises from a unique sequence of genetic lesions. Does each also have a unique metabolic signature? Most conclusions on this topic are drawn from studying isolated cancer cell lines, but tumor cells may execute metabolism differently in vivo. Matthew G. Vander Heiden of the Massachusetts Institute of Technology described rodent models of non-small cell lung carcinoma and pancreatic cancer, both driven by KRAS-activation and p53-knockout mutations. The first model had tumors characterized by increased glucose uptake; surprisingly, these tumors had elevated glucose catabolism through oxidative phosphorylation, in addition to elevated glycolytic metabolism. Glutamine tracing, however, showed almost no glutamine anaplerosis in vivo. But when explanted to culture conditions, cells from these tumors acquired glutamine dependence. In the pancreatic cancer model, no single nutrient was clearly favored as a metabolite. Albumin labeling experiments, however, showed that most of the pancreatic cancer cell biomass was derived from this extracellular protein.
It has long been assumed that extracellular protein is not a major fuel for most cells, but as Thompson observed, there is evidence that mammalian cells can draw on this energy source. Most cell culture media are supplemented with serum containing albumin, and the 0.74 mM concentration of albumin found in human plasma is equivalent to a 400 mM source of amino acids. The finding that cancer cells and cultured normal cells ingest extracellular protein through micropinocytosis has invigorated the field. The normal pathway to nutrient acquisition in slime molds, this process involves forming a vesicle around the extracellular contents and ingesting whatever is present in the surrounding media. The tumor cells in Vander Heiden's pancreatic cancer model fed biosynthesis and anaplerosis through this unusual process of macropinocytosis and protein catabolism.
Thompson's data show that mouse embryonic fibroblasts grown in leucine-depleted media cease proliferating. But their growth is rescued by the addition of albumin in excess of 3%. The addition of chloroquine to inhibit lysosomal proteolysis confirmed that albumin is metabolized via a macropinocytic mechanism; blocking the cell's ability to form lysosomal vesicles abrogated the albumin rescue. Alec C. Kimmelman of Harvard Medical School explained that autophagy, another lysosome-dependent pathway, could be a therapeutic target in cancers such as pancreatic adenocarcinoma. Activated KRAS–driven pancreatic cancers have historically been among the most difficult to treat, with a 5-year survival rate of 6%. Kimmelman's data show that genetic or pharmacologic inhibition of autophagy slows growth of pancreatic cancer cell lines and of tumors in genetically engineered mouse models. This work also demonstrates that autophagy has key roles in the metabolism of these tumors.
Altered metabolism facilitates the rapid proliferation of transformed cells; it is also implicated in metastasis and in the maintenance of pluripotency. Elena Piskounova of the University of Texas Southwestern Medical Center explained that successful metastasis, which is associated with worse cancer outcomes, is a relatively rare event; for every thousand cells that dissociate from a tumor, only one or two will successfully colonize a new site. Using a xenograft model with human melanoma cells introduced to immunocompromised mice, Piskounova showed that the limiting step in metastasis was cell survival in the circulatory system. Metabolic profiling revealed that these cells have high levels of oxidized glutathione and reactive oxygen species. Treatment of the xenografted mice with antioxidants increased the rate of metastasis, suggesting that, to survive, circulating tumor cells (CTCs) must overcome oxidative stress. Piskounova explained that cancer cells' need for NADPH, a reducing molecule that helps cells combat oxidative stress, might be met through folate metabolism.
If it survives oxidative stress, a CTC must adapt metabolically to the target tissue it colonizes. Sohail Tavazoie of the Rockefeller University studies how colon cancer–derived cells colonize the liver. A screen for microRNAs that suppress colon-to-liver metastasis identified mir-483 and mir-551a, which targeted the brain-type creatine kinase (CKB). Further study revealed that this kinase is secreted from cells and then converts creatine to phosphocreatine in an ATP-dependent reaction. Transport of the phosphocreatine back into the cells provides a catabolic substrate to fuel cellular energy and biosynthetic needs. Drugs that promote oxidative stress or block folate metabolism, NADPH production, or creatine utilization hold promise as therapies to prevent metastasis.
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Presentations available from:
John Blenis, PhD (Weill Cornell Medical College)
Lydia Finley, PhD (Memorial Sloan-Kettering Cancer Center)
Elena Piskounova, PhD (University of Texas Southwestern Medical Center)
Sohail Tavazoie, MD, PhD (The Rockefeller University)
Craig B. Thompson, MD (Memorial Sloan-Kettering Cancer Center)
How to cite this eBriefing
The New York Academy of Sciences. Cancer Cell Metabolism: Unique Features Inform New Therapeutic Opportunities. Academy eBriefings. 2015. Available at: www.nyas.org/TumorMetabolism-eB
Carey BW, Finley LW, Cross JR, et al. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature. 2015;518(7539):413-6.
Choo AY, Blenis J. TORgeting oncogene addiction for cancer therapy. Cancer Cell. 2006;9(2):77-9.
Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497(7451):633-7.
Galluzzi L, Pietrocola F, Bravo-San Pedro JM, et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015;34(7):856-80.
Hiller K, Metallo CM. Profiling metabolic networks to study cancer metabolism. Curr Opin Biotechnol. 2013;24(1):60-8.
Jiang X, Overholtzer M, Thompson CB. Autophagy in cellular metabolism and cancer. J Clin Invest. 2015;125(1):47-54.
Kamphorst JJ, Nofal M, Commisso C, et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 2015;75(3):544-53.
Kimmelman AC. Metabolic dependencis in RAS-driven cancers. Clin Cancer Res. 2015;21(8):1828-34.
Loo JM, Scherl A, Nguyen A, et al. Extracellular metabolic energetics can promote cancer progression. Cell. 2015;160(3):393-406.
Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36(6):320-8.
Metallo CM, Vander Heiden MG. Understanding metabolic regulation and its influence on cell physiology. Mol Cell. 2013;49(3):388-98.
Niesvizky R, Badros AZ, Costa LJ, et al. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma. 2015;15:1-9.
Palm W, Park Y, Wright K et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell. 2015;162(2):259-70.
Pencheva N, Tavazoie SF. Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol. 2013;15(6):546-54.
Quintana E, Piskounova E, Shackleton M, et al. Human melanoma metastasis in NSG mice correlates with clinical outcome in patients. Sci Transl Med. 2012;4(159):159.
Vander Heiden MG, Plas DR, Rathmell JC, et al. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol. 2001;21(17):5899-912.
Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21(3):297-308.
Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signaling. Nat Rev Mol Cell Biol. 2012;13(4):270-6.
Wise DR, Thompson CB. Glutamine addicitions: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427-33.
Lydia Finley, PhD
Memorial Sloan-Kettering Cancer Center
Lydia Finley is the Jack Sorrell Fellow of the Damon Runyon Cancer Research Foundation and a postdoctoral fellow in the laboratory of Dr. Craig Thompson at Memorial Sloan-Kettering Cancer Center. She earned her PhD in the laboratory of Dr. Marcia Haigis at Harvard Medical School. Her research focuses on how signaling events regulate intracellular metabolic pathways and how metabolites influence chromatin state and cell fate decisions.
Steven S. Gross, PhD
Steven S. Gross is a professor of pharmacology at the Weill Cornell Medical College and the director of the Mass Spectrometry Core Facility and of Advanced Training in Pharmacology. His expertise is in pharmacology and cell and structural biology, particularly in relation to the role of nitric oxide (NO) as a signaling molecule. In the late 1980s, Gross and colleagues made the initial identification of L-arginine as the precursor of NO in blood vessels. They were also first to establish that NOS inhibition elevates blood pressure in animals, demonstrating that NO plays a physiological role in controlling blood pressure and vascular tone. Since then, his research has aimed to elucidate the enzymes and mechanisms that regulate NO synthesis in cells. His basic studies have provided insights into the therapeutic control of NO synthesis, resulting in core technologies for the creation of ArgiNOx Inc., a biotech start-up that seeks to develop novel NO-based drugs. Gross received his PhD in biomedical science from Mount Sinai School of Medicine.
Costas A. Lyssiotis, PhD
Costas Lyssiotis recently joined the faculty at the University of Michigan Medical School as an assistant professor with appointments in the Departments of Physiology and Medicine. He studies the biochemical pathways and metabolic requirements that enable tumor survival and growth and how this information can be used to design targeted therapies. Lyssiotis demonstrated that pancreatic cancers are addicted to glucose and glutamine and use these nutrients in previously undescribed pathways to make DNA and to generate free radical–combating antioxidants, respectively. He has been awarded a Pathway to Leadership Grant from the Pancreatic Cancer Action Network, the Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation, and the Tri-Institutional Breakout Prize for Junior Investigators. Lyssiotis received his PhD in chemical biology at the Scripps Research Institute and completed a postdoctoral fellowship with Dr. Lewis Cantley at Weill Cornell Medical College.
Sonya Dougal, PhD
The New York Academy of Sciences
Sonya Dougal is the director of Life Sciences Discussion Groups at the New York Academy of Sciences. She develops an annual portfolio of scientific symposia on life sciences and biomedical research. Dougal has over 14 years of experience in scientific research and program management in academia, industry, and nonprofits. She holds a PhD in cognitive psychology from the University of Pittsburgh. She was the recipient of a Ruth L. Kirschstein National Research Service Award from the National Institutes of Health for her postdoctoral training as a cognitive neuroscientist in the laboratory of Dr. Elizabeth Phelps at New York University.
Craig B. Thompson, MD
Craig B. Thompson is the president and chief executive officer of Memorial Sloan-Kettering Cancer Center (MSKCC). Thompson is a board-certified internist and medical oncologist with extensive research experience in cancer, immunology, and translational medicine. His current research focuses on the regulation of cellular metabolism during cell growth/differentiation and on the role that metabolic changes play in the origin and progression of cancer. Thompson is a member of the Institute of Medicine, the National Academy of Sciences, the American Academy of Arts and Sciences, and the Medical Advisory Board of the Howard Hughes Medical Institute. He holds an MD from the University of Pennsylvania.
John Blenis, PhD
John Blenis is the Anna-Maria and Stephen Kellen Professor of Cancer Research and a professor of pharmacology at Weill Cornell Medical College. He completed his PhD at Michigan State University and his postdoctoral research at Harvard University. Blenis was an assistant professor at Northwestern University and then assistant, associate, and tenured professor of cell biology at Harvard Medical School before moving to the Meyer Cancer Center at Weill Cornell. His research aims to define and characterize the molecular basis of cellular signaling with a focus on the Ras-ERK-RSK and PI3K-mTOR-S6K1 pathways. He studies how these signaling systems contribute to normal and disease-associated physiology, with a focus on cancer and cancer therapy.
Selina Chen-Kiang, PhD
Weill Cornell Medical College
Selina Chen-Kiang is a professor of pathology and of immunology and microbial pathogenesis at the Weill Cornell Medical College. She obtained her PhD in human genetics and development from Columbia University and completed postdoctoral training in molecular biology at The Rockefeller University. Her work focuses on cell cycle control of B cell immunity and malignancies, particularly reprogramming cancer cells by cell cycle. Her team developed of the first mechanism-based combination cell cycle therapy in human cancer. She also studies cell cycle control of therapeutic targeting of PI3K and BTK, as well as metabolism and drug resistance in lymphoma and myeloma. Chen-Kiang is the recipient of a Specialized Center for Research Award and of a Researcher of the Year award from the Leukemia and Lymphoma Society.
Lydia Finley, PhD
Memorial Sloan-Kettering Cancer Center
Alec C. Kimmelman, MD, PhD
Alec C. Kimmelman is an associate professor of radiation oncology at the Dana-Farber Cancer Institute at Harvard Medical School. He received his MD and PhD from Mount Sinai School of Medicine, completed residency training at the Harvard Radiation Oncology Program, and did postdoctoral work at the Dana-Farber Cancer Institute, where he identified novel genes that are important in the invasive and metastatic phenotype of pancreatic cancer. Kimmelman is an attending radiation oncologist at the Dana-Farber Cancer Institute and Brigham and Women's Hospital, specializing in gastrointestinal malignancies, and the director of preclinical therapeutics of the small animal microirradiator facility. Kimmelman is the recipient of the Ruth Leff Siegal Award from Columbia University for excellence in pancreatic cancer research.
Christian Metallo, PhD
Christian Metallo is an assistant professor in the Department of Bioengineering at the University of California, San Diego. He received his Bachelor's degree in chemical engineering from the University of Pennsylvania before joining Merck Research Laboratories to conduct bioprocess engineering research. He received his PhD from the University of Wisconsin–Madison Department of Chemical and Biological Engineering in 2008 and completed an American Cancer Society postdoctoral fellowship in chemical engineering at the Massachusetts Institute of Technology. Metallo received the Biomedical Engineering Society Rita Schaffer Young Investigator Award in 2012. He was a 2013 Searle Scholar.
Elena Piskounova, PhD
University of Texas Southwestern Medical Center
Elena Piskounova is a Helen Hay Whitney Fellow in the laboratory of Dr. Sean J. Morrison at the Children's Research Institute at the University of Texas Southwestern Medical Center. She studies the metabolic requirements and adaptations that occur in cancer cells during distinct steps of the metastatic cascade, using a clinically relevant model of melanoma. She aims to uncover and validate novel therapeutic targets for metastatic disease. Piskounova completed her PhD in biological and biomedical sciences at Harvard Medical School, where she studied the molecular mechanisms that mediated posttranscriptional processing of the let-7 family of microRNAs by the Lin28 oncoproteins. She also holds a Master's degree in molecular and cellular biochemistry from the University of Oxford, UK.
Sohail Tavazoie, MD, PhD
Sohail Tavazoie received his PhD from Harvard University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology. After a residency and internship in internal medicine at Brigham and Women's Hospital, Tavazoie joined Memorial Sloan-Kettering Cancer Center as a clinical fellow in 2005 and became a research fellow in medical oncology in 2006. He joined Rockefeller as an assistant professor in 2009 and became an associate professor in 2015. Tavazoie is a recipient of the NIH Director's New Innovator Award and of a combined American Society of Clinical Oncology and American Association for Cancer Research Young Investigator Award. He was a Rita Allen Foundation Scholar, a Sidney Kimmel Foundation for Cancer Research Scholar, and a Department of Defense Era of Hope Scholar. Tavazoie is an attending medical oncologist at Memorial Sloan-Kettering Cancer Center.
Matthew G. Vander Heiden, MD, PhD
Matthew Vander Heiden is the Eisen and Chang Associate Professor in the Koch Institute for Integrative Cancer Research and the Department of Biology at the Massachusetts Institute of Technology. He is also an instructor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School. Vander Heiden received his MD and PhD degrees from the University of Chicago. He also completed clinical training in internal medicine and medical oncology at the Brigham and Women's Hospital and Dana-Farber Cancer Institute and a postdoctoral fellowship at Harvard Medical School. His laboratory is using biochemical approaches to understand the pathway biochemistry of proliferating cells, testing the hypothesis that cell growth signals reprogram metabolism to support the distinct energetic needs of proliferating cells.
Paul Riccio is a postdoctoral research scientist at Columbia University. He has a broad interest in the genetic regulation of development and is currently using new genetic techniques to study kidney patterning and regeneration.