Exposing Vulnerabilities in Cancer Metabolism: New Discoveries

Exposing Vulnerabilities in Cancer Metabolism: New Discoveries

Monday, May 16, 2016

The New York Academy of Sciences

Presented By

Hot Topics in Life Sciences

 

There has been a resurgence of interest in understanding how metabolic pathways are altered in cancer and how these alterations can be exploited for therapeutic gain. However, because normal cells and cancer cells often require the same energy sources and metabolic pathways, designing metabolism-based cancer therapies without systemic toxicity has proven challenging. The goal of this meeting is to bring experts together to discuss recent findings suggesting that discrete metabolic pathways and activities are over-utilized in certain cancer contexts, leaving cancer cells selectively vulnerable to specific metabolic interventions. This symposium will highlight insights into tumor metabolism from leaders in the field and explore how this information is being used to design safe and effective metabolism-targeted therapies.

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Agenda

* Presentation titles and times are subject to change.


May 16, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Costas Andreas Lyssiotis, PhD, University of Michigan Medical Center

Keynote Lecture

9:15 AM

Large Scale Approaches to Study Cancer Dependencies
David Sabatini, MD, PhD, Whitehead Institute and the Massachusetts Institute of Technology

Session 1

10:00 AM

mTOR Connects Oncogenic Signaling to Anabolic Metabolism
Brendan Manning, PhD, Harvard T.H. Chan School of Public Health

10:30 AM

Coffee Break

11:00 AM

Autophagy Prevents Fatal Nucleotide Pool Depletion in Ras-driven Cancer Cells
Eileen White, PhD, Rutgers Cancer Institute of New Jersey

11:30 AM

New Regulation of Lipid Metabolism in Cancer
Marcia Haigis, PhD, Harvard Medical School

12:00 PM

Networking Lunch and Poster Session

Session 2

1:30 PM

Synthetic Lethality in KRas-driven Cancer Cells Created by Glutamine Deprivation
David A. Foster, PhD, Hunter College of the City University of New York

2:00 PM

Elucidating the Fate of Mitochondrial Folate-mediated 1-C Units in Cancer and Embryogenesis Using Untargeted Stable Isotope Tracing
Steven Gross, PhD, Weill Cornell Medical Center

2:30 PM

Coffee Break

3:00 PM

Probing Metabolism in vivo with Hyperpolarized MRI
Kayvan Keshari, PhD, Memorial Sloan Kettering Cancer Center

3:30 PM

An Essential Function of Mitochondrial Respiration in Cell Proliferation
Kivanc Birsoy, PhD, The Rockefeller University

Keynote Lecture

4:00 PM

Systems-level Analysis of Metabolic Regulation from Yeast to Cancer
Joshua Rabinowitz, MD, PhD, Princeton University

4:45 PM

Closing Remarks
Lydia Finley, PhD, Memorial Sloan Kettering Cancer Center

5:00 PM

Networking Reception

6:00 PM

Adjourn

Organizers

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 Craig Thompson at Memorial Sloan Kettering Cancer Center. She earned her PhD in the laboratory of Marcia Haigis at Harvard Medical School. Her research focuses on understanding how signaling events regulate intracellular metabolic pathways and how metabolites influence chromatin state and cell fate decisions.

Steven S. Gross, PhD

Weill Cornell Medical College

Dr. Steven S. Gross is Professor of Pharmacology, Director of Advanced Training in Pharmacological Sciences, and Metabolomics Lab Director at Weill Cornell Medical College. His major research interest over the past two decades has been elucidating mechanisms of cell signaling by reactive molecules, with a primary focus on the physiological chemistry and biology of nitric oxide (NO). Work on NO has culminated in over 170 published papers, 25 issued US patents, and the founding of a biotech start-up that conducted a multinational phase III clinical study to test the therapeutic efficacy of a NO synthase (NOS) inhibitor for a life-saving cardiovascular indication. With Nobel Laureates in the field, Dr. Gross founded the NO Society. Since reactive molecules typically mediate their cell signaling actions by engaging in covalent reactions with proteins, he sought to develop proteomic approaches that can be used to define and inventory various NO-mediated protein modifications. These efforts led to an interest in biological mass spectrometry (MS) and his establishment in 1997 of the MS core facility at Weill Cornell Medical College. His lab acquired broad experience and know-how in bioanalytical techniques for protein and small molecule analysis –including a robust platform for untargeted metabolite profiling and development of an untargeted stable isotope tracing technology.

Costas Andreas Lyssiotis, PhD

University of Michigan

Costas A. Lyssiotis obtained his bachelor's degree in chemistry and biochemistry from the University of Michigan in 2004 and his PhD in Chemical Biology from The Scripps Research Institute in 2010. Costas joined the laboratory of Lewis C. Cantley at Harvard Medical School as the Amgen fellow of the Damon Runyon Cancer Research Foundation and was later awarded a Pancreatic Cancer Action Network Pathway to Leadership Grant. Dr. Lyssiotis is currently an Assistant Professor at the University of Michigan Medical School with appointments in the Departments of Physiology and Medicine. His lab studies the biochemical pathways and metabolic requirements that enable tumor survival and growth and, in particular, how this information can be used to design targeted therapies. He is a Lefkofsky Scholar, a Kimmel Scholar a Dale F. Frey Breakthrough Scientist and was awarded the Tri-Institutional Breakout Prize for Junior Investigators.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Speakers

Kivanc Birsoy, PhD

The Rockefeller University

Kivanc Birsoy received his undergraduate degree in Molecular Genetics from Bilkent University in Turkey in 2004 and his PhD from the Rockefeller University in 2009, where he studied molecular genetics of obesity in the laboratory of Jeffrey Friedman. In 2010, he joined the laboratory of David Sabatini at the Whitehead Institute of Massachusetts Institute of Technology (MIT). There, he combined forward genetics and metabolomics approaches to understand how different cancer types rewire their metabolism to adapt nutrient deprived environments. He also used similar approaches to study how mitochondrial dysfunction influences cellular metabolism. In 2015, Dr. Birsoy joined the Rockefeller faculty as an Assistant Professor. He is a recipient of Jane Coffin Childs Medical Fund Fellowship, Leukemia and Lymphoma Society Special Fellow award, Searle Scholar award, Sidney Kimmel Foundation award and NIH Career Transition award.

David A. Foster, PhD

Hunter College of the City University of New York

David Foster is the Rosalyn Yalow Professor in the Department of Biological Sciences at Hunter College of the City University and holds an adjunct faculty position in the Department of Pharmacology and Weill Cornell Medicine where his lab recently moved. He received his Bachelor's degree in Biochemistry from the University of California at Berkeley and his PhD from Columbia University where he studied DNA synthesis with Geoffrey Zubay. His postdoctoral studies were worked in the lab of Saburo Hanafusa at the Rockefeller University where he worked with RNA tumor viruses expressing oncogenic tyrosine kinases. Upon establishing his own lab, he began investigating the intracellular signals that are activated by oncogenic tyrosine kinases and discovered that a common target of these signals is the enzyme phospholipase D (PLD). Elevated PLD expression and activity has subsequently been found in virtually every cancer where it has been examined. The metabolite generated by PLD is phosphatidic acid (PA), which is required for mTOR and much of his work over the past 15 years has been examining the PA-mTOR signaling axis in human cancer cells. His work has also involved dysregulated metabolic control of cell cycle progression in cancer cells.

Steven S. Gross, PhD

Weill Cornell Medical College

Dr. Steven S. Gross is Professor of Pharmacology, Director of Advanced Training in Pharmacological Sciences, and Metabolomics Lab Director at Weill Cornell Medical College. His major research interest over the past two decades has been elucidating mechanisms of cell signaling by reactive molecules, with a primary focus on the physiological chemistry and biology of nitric oxide (NO). Work on NO has culminated in over 170 published papers, 25 issued US patents, and the founding of a biotech start-up that conducted a multinational phase III clinical study to test the therapeutic efficacy of a NO synthase (NOS) inhibitor for a life-saving cardiovascular indication. With Nobel Laureates in the field, Dr. Gross founded the NO Society. Since reactive molecules typically mediate their cell signaling actions by engaging in covalent reactions with proteins, he sought to develop proteomic approaches that can be used to define and inventory various NO-mediated protein modifications. These efforts led to an interest in biological mass spectrometry (MS) and his establishment in 1997 of the MS core facility at Weill Cornell Medical College. His lab acquired broad experience and know-how in bioanalytical techniques for protein and small molecule analysis –including a robust platform for untargeted metabolite profiling and development of an untargeted stable isotope tracing technology that will be the focus of his NYAS presentation.

Marcia Haigis, PhD

Harvard Medical School

Marcia C. Haigis obtained her PhD in Biochemistry from the University of Wisconsin in 2002. She then performed postdoctoral research at MIT studying mitochondrial regulation and aging. In 2006, Dr. Haigis joined the faculty of Harvard Medical School, where she is currently an Associate Professor in the Department of Cell Biology. Additionally, Dr. Haigis is an active member of the Paul F. Glenn Laboratories for Medical Research and organizes a Boston Area Aging Data community. Her current work contributes to the molecular understanding of how mitochondria regulate cellular stress responses in cancer. For her work, Dr. Haigis has received a Brookdale Leadership in Aging Award, the Ellison Medical Foundation New Scholar Award and an American Cancer Society Research Scholar Award.

Kayvan R. Keshari, PhD

Memorial Sloan Kettering Cancer Center

Dr. Kayvan R. Keshari received degrees in Biochemistry, Mathematics and Biomedical Engineering from the University of California, Berkeley and University of North Carolina, respectively, after which he completed postdoctoral training at the University of California, San Francisco (UCSF) in Biomedical imaging and Bioengineering under the supervision of Dr. John Kurhanewicz. He is currently an Assistant Member and Laboratory Head at Memorial Sloan Kettering Cancer Center, with appointments in both the Department of Radiology and the Molecular Pharmacology Program. He is a professor in the Gerstner Sloan Kettering School of Biomedical Sciences and in multiple departments with Cornell University including Chemical Biology and Biochemistry. At MSK, Dr. Keshari's lab focuses on the interrogation of cancer metabolic processes and advanced multi-modality imaging, with special emphasis in the field of hyperpolarized MRI. With changes in cancer metabolism as the driving force, the lab's biochemical investigation is centered on oxidative stress and changes in redox, as well as the rates of biochemical reactions in vivo, which are related to cancer aggressiveness and response to therapeutics. The long-term goal of which is to bring some of these novel mechanisms to the clinic and make an impact on both diagnosis and therapy.

Brendan D. Manning, PhD

Harvard T.H. Chan School of Public Health

Brendan Manning is a Professor in the Department of Genetics and Complex Diseases at Harvard University's T.H. Chan School of Public Health, Director of the PhD Program in Biological Sciences in Public Health at Harvard's Graduate School of Arts and Sciences, and a Faculty Member of the Dana-Farber/Harvard Cancer Center. Dr. Manning received his BS from the University of Massachusetts, Amherst and his PhD from Yale University in 2000. He then joined the laboratory of Lewis Cantley at Harvard Medical School for his postdoctoral research. During this time, he discovered that the tuberous sclerosis complex (TSC) tumor suppressors serve as the molecular connection between the PI3K and mTOR pathways, thereby linking a signaling pathway activated in the majority of human cancers to a nutrient-sensing pathway that controls cell growth and metabolism. In 2004, he joined the faculty of the then newly established Department of Genetics and Complex Diseases at Harvard to continue research at the interface of cancer and metabolism. In 2015, Dr. Manning became an inaugural recipient of the National Cancer Institute's Outstanding Investigator Award.

Joshua Rabinowitz, MD, PhD

Princeton University

Joshua Rabinowitz grew up in Chapel Hill, North Carolina. In 1994, he earned BA degrees in Mathematics and Chemistry from the University of North Carolina. From there, he moved west to Stanford, where he earned his PhD in Biophysics in 1999, followed by his MD in 2001. In 2000, he co-founded Alexza Pharmaceuticals leading R&D efforts there for four years, eventually resulting in FDA approval of the first thermal aerosol drug delivery product, the Adasuve inhaler. In 2004, Joshua joined the faculty of Princeton University, where he established a leading research group in the area of metabolomics. His lab has developed innovative ways to use isotope tracers to map metabolic flows (fluxes), and has blended these technologies with state-of-the-art genetics and computation to reveal normal metabolic regulation and dysregulation in disease. These technologies have contributed to important biomedical advances, including the discovery of the oncometabolite 2-hydroxyglutarate, and to the founding of multiple companies, most recently Raze Therapeutics. Joshua is author of more than 100 papers and the inventor of over 100 patents.

David M. Sabatini, MD, PhD

Whitehead Institute

David Sabatini is a Member of the Whitehead Institute for Biomedical Research, Senior Associate Member at The Broad Institute MIT, and Member of the Koch Institute for Integrative Cancer Research at MIT, as well as a Professor of Biology at the Massachusetts Institute of Technology. He is also Investigator of the Howard Hughes Medical Institute. David received his BS from Brown University magna cum laude and his MD/PhD from Johns Hopkins University in 1997. He completed his thesis work in the lab of Dr. Solomon H. Snyder in the Department of Neuroscience. Later in the same year, David was appointed a Whitehead Fellow at the Whitehead Institute for Biomedical Research. This was followed in 2002 by a dual appointment as a Member at the Whitehead Institute and Assistant Professor of Biology at the Massachusetts Institute of Technology. David has received a number of distinctions, including being named a W. M. Keck Foundation Distinguished Young Scholar, a Pew Scholar, a TR100 Innovator, a recipient of the 2009 Paul Marks Prize for Cancer Research, 2012 The Earl and Thressa Stadtman Scholar Award from ASBMB, 2013 Feodor Lynen Award from Nature, the 2014 NAS Award in Molecular Biology, the 2014 Colin Thomson Memorial Medal, and most recently, he was named the Alexander M. Cruickshank Lecturer at the Gordon Research Conference on Lysosomal Diseases, Galveston, TX.

David and his lab at the Whitehead Institute study the basic mechanisms that regulate cell growth, the process whereby cells and organisms accumulate mass and increase in size. These pathways are often deranged in human diseases, such as diabetes and cancer. A major focus of the lab is on a cellular system called the Target of Rapamycin (TOR) pathway, a major regulator of growth in many eukaryotic species. Work in David's lab has led to the identification of many components of the pathway and to an understanding of their cellular and organismal functions. David is also interested in the role of metabolism in cancer and in the mechanisms that control the effects of dietary restriction on tumorigenesis. In addition to the work on growth control and cancer, David's lab has developed and is using new technologies that facilitate the analysis of gene function in mammalian cells. The lab developed 'cell-based microarrays' that allow one to examine the cellular effects of perturbing the activity of thousands of genes in parallel. David is a founding member of The RNAi Consortium (TRC) of labs in the Boston area that is developing and using genome-scale RNA interference (RNAi) libraries targeting human and mouse genes.

Eileen White, PhD

Rutgers University

Dr. Eileen White received her Bachelor of Science degree from Rensselaer Polytechnic Institute followed by a PhD in Biology from SUNY Stony Brook. She went on to be a Damon Runyon Postdoctoral fellow in the laboratory of Dr. Bruce Stillman and then to a Staff Investigator position at Cold Spring Harbor Laboratory. There she discovered that one of the oncogenes of the DNA tumor virus adenovirus encoded an inhibitor of programmed cell death or apoptosis (E1B 19K) that this gene was a viral homologue of the human BCL-2 oncogene. She went on to establish that oncogene activation that deregulates cell growth also activates apoptosis, and that coordinate inhibition of apoptosis is an important function that promotes cancer. These findings revealed roles for the p53 tumor suppressor in activating apoptosis and suppressing cancer and for the Bcl-2-related anti-apoptotic proteins blocking apoptosis and promoting cancer.

Dr. White continued her work defining the role and mechanisms of apoptosis regulation in cancer at Rutgers University where she is currently the Deputy Director and Associate Director for Basic Science at the Rutgers Cancer Institute of New Jersey, an NCI-designated Comprehensive Cancer Center. She is also a Distinguished Professor of Molecular Biology and Biochemistry. Dr. White has served on the Board of Scientific Counselors of the National Cancer Institute and other review panels for the National Institutes of Health. She is the recipient of numerous awards including a MERIT award from the National Cancer Institute, the Red Smith award from the Damon Runyon Cancer Research Foundation, a Howard Hughes Medical Institute Investigatorship, an Achievement Award from the International Cell Death Society, a Career Award for the European Cell Death Organization, and is an elected Fellow of the American Society of Microbiology (ASM) and the American Association for the Advancement of Science (AAAS). Dr. White has also served as a member of the Board of Directors of the American Association for Cancer Research (AACR), the Scientific Review Boards for the Starr Cancer Consortium, the Damon Runyon Cancer Research Foundation, and the Cancer Prevention Research Institute of Texas (CPRIT). She is on the External Advisory Boards of the Yale, Case, and MGH Comprehensive Cancer Centers.

Abstracts

Large Scale Approaches to Study Cancer Dependencies
David M. Sabatini, MD, PhD, Whitehead Institute

mTOR is the target of the immunosuppressive and anti-cancer drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has key roles in the control of metabolism, cell and organ size, and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival and metabolism through Akt. These complexes, called mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. Over the last few years we have focused on how nutrients, particularly amino acids, regulate mTORC1. We have identified a complex signaling pathway that relays amino acid availability to mTORC1 through the heterodimeric Rag GTPases. We recently discovered several of the amino acid sensors for the pathway. I will discuss new results from our lab on the regulation and functions of mTORC1.
 
1) Saxton, R.A., Knockenhauer, K.E., Wolfson, R.L., Chantranupong, L., Pacold, M.E., Wang, T., Schwartz, T.U., Sabatini, D.M. (2015) Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 2015 Nov 19. pii: aad2087 [Epub ahead of print]
 
2) Wolfson, R.L., Chantranupong, L., Saxton, R.A., Shen, K., Scaria, S.M., Cantor, J.R., Sabatini, D.M. (2015) Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 2015 Oct 8. pii: aab2674. [Epub ahead of print]
 
3) Wang, S., Tsun, Z., Wolfson, R.L., Shen, K., Wyant, G.A., Plovanich, M.E., Yuan, E.D., Jones, T.D., Chantranupong, L., Comb, W., Wang, T., Bar-Peled, L., Zoncu, R., Straub, C., Kim, C., Park, J., Sabatini, B.L., Sabatini, D.M. (2015) Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347: 188-194.
 
4) Bar-Peled, L., Chantranupong, L., Cherniack, A.D., Chen, W.W., Ottina, K.A., Grabiner, B.C, Spear, E.D., Carter, S.L., Meyerson, M., Sabatini, D.M., (2013) A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340: 1100-1106.
 
5) Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A.L., Nada, S. and Sabatini, D.M. (2010) Ragulator-Rag Complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141: 290-303.

mTOR Connects Oncogenic Signaling to Anabolic Metabolism
Brendan D. Manning, PhD, Harvard T.H. Chan School of Public Health

Metabolic processes within cells must be managed by integrated control mechanisms that sense the nutrient status of both the cell and organism. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients and other growth signals to the coordinated regulation of cellular metabolism. Through a variety of common oncogenic events influencing its upstream regulation, mTORC1 is often aberrantly activated in cancer cells, resulting in cellular autonomy from normal growth control mechanisms. The physiological and pathological activation of mTORC1 results in a shift from catabolic processes to anabolic biosynthetic processes. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and organisms, including the de novo synthesis of proteins, lipids, and nucleotides. I will discuss our latest data on the role of mTORC1 in driving an integrated metabolic program that underlies the aberrant growth of cancer cells. This talk will have a particular emphasis on our latest findings related to the control of nucleotide synthesis.

Autophagy Prevents Fatal Nucleotide Pool Depletion in Ras-driven Cancer Cells
Eileen White, PhD, Rutgers University

Autophagy degrades and recycles proteins and organelles essential for quality control and survival in starvation. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes tumor growth and malignancy. Autophagy-deficient tumor-derived cell lines (TDCLs) are respiration impaired, starvation sensitive, and glutamine-dependent. To survive starvation, autophagy may eliminate defective mitochondria or supply mitochondrial substrates. Here, we sequenced the mitochondrial genome from Kras-driven lung tumors and found higher mutant allele frequencies without autophagy-related-7 (Atg7). But the low pathogenic allele frequency was insufficient to account for metabolic defects. In starvation, Atg7 deficiency attenuated substrate supply for mitochondrial oxygen consumption and increased nucleotide degradation. The resulting nucleotide pool depletion and energy crisis in starvation was rescued by nucleoside supplementation. Thus the role for autophagy in Kras-driven tumor cells is to provide substrates to mitochondria to maintain nucleotide pools and energy homeostasis, which promotes survival to nutrient limitation.

New Regulation of Lipid Metabolism in Cancer
Marcia Haigis, PhD, Harvard Medical School

Cancer cells metabolize large quantities of nutrients to support their requirements for survival and rapid proliferation. While much research has examined the use of glucose and glutamine by tumor cells, a subset of cancers rely on fatty acid metabolism for their survival and growth, but our understanding of pathways that drive dependency on fatty acid oxidation in cancer is limited. Prolyl hydroxylase domain proteins (PHDs) hydroxylate substrate proline residues and have been linked to fuel switching in cancer. Here we will discuss a new substrate for PHD3 its role in tumors dependent on fatty acid catabolism. We have discovered that PHD3 hydroxylates acetyl-CoA carboxylase (ACC2), which controls the rate-limiting step of mitochondrial fat oxidation. PHD3 expression is strongly decreased in acute myeloid leukemia (AML), which also display reduced ACC2 hydroxylation, increased fat catabolism and sensitivity to treatment with FAO inhibitors. Thus, loss of PHD3 enables greater utilization of fatty acids as fuel, but also may serve as a metabolic liability by indicating cancer cell susceptibility to FAO inhibition.

Synthetic Lethality in KRas-driven Cancer Cells Created by Glutamine Deprivation
David A. Foster, PhD, City University of New York and Weill Cornell Medicine

Glutamine (Q) deprivation ordinarily causes a late G1 cell cycle arrest that can be distinguished from the mid G1 growth factor dependent restriction point and from a very late G1 checkpoint mediated by mTOR. However, cancer cell lines harboring KRas mutations bypass the Q-dependent G1 checkpoint and arrest instead in S-phase. Similarly, blocking anaplerotic utilization of Q with the transaminase inhibitor amino oxyacetate mimicked Q deprivation—causing S-phase arrest in K-Ras mutant cancer cells. The S-phase arrest was caused by the lack of aspartate generated by the transamination reaction whereby glutamate is converted to α-ketoglutarate with concomitant conversion of oxaloacetate to aspartate. The lack of aspartate interfered with purine and pyrimidine nucleotide biosynthesis—leading to S-phase arrest. Of potential significance, Q deprivation or suppression of Q utilization created a synthetic lethality for rapamycin, which is cytotoxic for cells arrested in S-phase. Q deprivation also created a synthetic lethality for the cell cycle phase-specific cytotoxic drugs, capecitabine and paclitaxel. These data demonstrate that disabling of the G1 Q checkpoint represent a novel vulnerability of cancer cells harboring KRas and possibly other mutations that disable the Q-dependent checkpoint.
 
Coauthors: Mahesh Saqcena1,2, Suman Mukhopadhyay1,3, Deven Patel1,2, Deepak Menon1,2, Elyssa Bernfeld1,3, Victoria Mroz1, Sampada Kalan1,3, and Diego Loayza1,2,3.
 
1. Department of Biological Sciences, Hunter College of the City University of New York.
2. Biochemistry Program, Graduate Center, of the City University of New York.
3. Biology Program, Graduate Center, of the City University of New York.
4. Department of Pharmacology, Weill Cornell Medicine, New York.

Elucidating the Fate of Mitochondrial Folate-mediated 1-C Units in Cancer and Embryogenesis Using Untargeted Stable Isotope Tracing
Steven S. Gross, PhD, Weill Cornell Medical College, New York

Folates are a family of inter-convertible species that serve as essential cofactors for one-carbon (1-C) trafficking in cells, required for de novo synthesis of purines, thymidine and S-adenosylmethionine (the direct donor of methyl groups for transfer to DNA, protein and lipids). The dominant cell source of 1-C units for trafficking by folates is the amino acid serine. Serine arises both as a glycolytic intermediate, and via extracellular uptake, followed by conversion to glycine within mitochondria by the action of SHMT2 - this initiates a cascade of folate-dependent reactions, culminating in formate release from mitochondria. This released formate serves as the major source of 1-C units for subsequent folate-dependent reactions in cytosol. Another apparent function of mitochondrial serine metabolism is as an important source of cellular reducing equivalents, in the form of NADPH. Importantly, the rate of cancer cell proliferation (and presumably rapid cell proliferation during embryogenesis) is proportional to serine uptake/synthesis and mitochondrial conversion to formate. Accordingly, enzymes involved in serine/folate-mediated formate synthesis and use are recognized as potential targets for cancer chemotherapy. Given the fundamental role of 1-C units for cancer cell proliferation, we sought to broadly uncover the metabolic fluxes of serine/formate-derived1-C units into alternative metabolic fates over time. One question we sought to answer was, what is the most immediate fate for 1-C units in cancer cells? Toward this end, we established a novel approach for untargeted stable isotope tracing and applied it for in vitro cell fate tracing of [13C]-serine and [13C]-formate. Findings will be presented.
 
Coauthor: Qiuying Chen, PhD, Weill Cornell Medical College, New York

Probing Metabolism in vivo with Hyperpolarized MRI
Kayvan R. Keshari, PhD, Memorial Sloan Kettering Cancer Center

Oncogenic transformation has been shown to have a dramatic impact on the metabolic state of the cell. Recent reports have demonstrated that specific alterations in oncogenes and signaling pathways results in increases in pathway flux as well as diversion of substrates. Interrogation though of these pathways in relevant systems has been hindered though by lack of versatile technologies capable of monitoring metabolism. Hyperpolarized magnetic resonance (HP MR) addresses a fundamental limitation of MRI for interrogating metabolic substrates, sensitivity. Using this approach, one can take endogenous metabolic substrates and generate a hyperpolarized state prior to infusion into a living system, creating a system with dramatically increased signal. These probes can then be followed using spectroscopic imaging techniques non-invasively and inform on the metabolic state of the cell as well as the dynamics of metabolism in real-time. In the setting of cancer metabolism, many biochemical probes have been developed which inform on multiple pathways. The realization of this method’s utility though is in its translation to use in man, which will support the interest for future development in this field. In this talk I will discuss our efforts to take this approach from the bench to man, from characterizing cells and mice to imaging humans, as well as our first insights into the critical methods necessary to make this adaptable for widespread application in future directions.

An Essential Function of Mitochondrial Respiration in Cell Proliferation
Kivanc Birsoy, PhD, The Rockefeller University

The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from donors like NADH to oxygen, the ultimate electron acceptor. Many metabolic pathways, including glycolysis, the TCA cycle, and beta-oxidation, produce the electron donors that fuel the ETC. In turn, ETC activity impacts a variety of processes beyond energy balance, such as reactive oxygen species (ROS) production, the redox state, mitochondrial membrane potential, mitochondrial protein import, cell death, and signaling. Dysfunctional ETC is involved in diverse pathologies like cancer and neurodegeneration but in most cases it is unclear how ETC dysfunction leads to the specific symptom. We recently found that the key function of ETC in cell proliferation is aspartate synthesis. Building upon this observation, our lab aims to understand how ETC dysfunction influences cellular process and results in diverse disease pathologies of cancer and mitochondrial disorders.

Systems-level Analysis of Metabolic Regulation from Yeast to Cancer
Joshua Rabinowitz, MD, PhD, Princeton University

Cellular metabolic fluxes are determined by enzyme activities and metabolite abundances. Biochemical approaches reveal the impact of specific substrates or regulators on enzyme kinetics, but do not capture the extent to which metabolite and enzyme concentrations vary across physiological and pathological states, nor the ability of a single reaction to impact pathway flux. Thus, quantitative control of metabolic activity in living cells remains largely an open question. Here I will discuss two approaches to deciphering cellular metabolic regulation. The first method, Systematic Identification of Meaningful Metabolic Enzyme Regulation (SIMMER), involves measurement of enzyme and metabolite concentrations and metabolic fluxes across many experimental conditions. The resulting cellular data are then used to deduce, for many reactions in parallel, a Michaelis-Menten relationship between enzyme, substrate, product, and potential regulator concentrations. The SIMMER method will be demonstrated using data from yeast chemostat cultures, where it revealed three new instances of cross-pathway allosteric regulation. Moreover, it showed that, overall substrate concentrations are the strongest driver of fluxes, with metabolite levels collectively exerting more than double the flux control of enzymes. The second method, involving determining the metabolite concentration and flux impact of overexpressing each enzyme in a pathway individually, looks to identify all pathway reactions capable of controlling overall flux. It will be demonstrated using data from glycolysis and the pentose phosphate pathway in transformed renal epithelial cells, where it reveals a predominant role for glucose uptake and phosphorylation to glucose-6-phosphate and fructose-1, 6-bisphosphate in controlling glycolytic flux. Together, these approaches highlight the potential for systems-level manipulation and measurement of enzymes, metabolites, and fluxes to elucidate metabolic regulation.

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