171 results on '"Pacold, Michael E."'
Search Results
2. Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma
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Zhao, Guisheng, Newbury, Patrick, Ishi, Yukitomo, Chekalin, Eugene, Zeng, Billy, Glicksberg, Benjamin S., Wen, Anita, Paithankar, Shreya, Sasaki, Takahiro, Suri, Amreena, Nazarian, Javad, Pacold, Michael E., Brat, Daniel J., Nicolaides, Theodore, Chen, Bin, and Hashizume, Rintaro
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- 2022
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3. Abstract IA026: Metabolic dependencies of brain metastases
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Pacold, Michael E, primary
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- 2024
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4. DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy
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Lin, Hsin-Pin, primary, Petersen, Jennifer D., additional, Gilsrud, Alexandra J., additional, Madruga, Angelo, additional, D’Silva, Theresa M., additional, Huang, Xiaoping, additional, Shammas, Mario K., additional, Randolph, Nicholas P., additional, Li, Yan, additional, Jones, Drew R., additional, Pacold, Michael E., additional, and Narendra, Derek P., additional
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- 2024
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5. The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway
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Banh, Robert S., Kim, Esther S., Spillier, Quentin, Biancur, Douglas E., Yamamoto, Keisuke, Sohn, Albert S. W., Shi, Guangbin, Jones, Drew R., Kimmelman, Alec C., and Pacold, Michael E.
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- 2021
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6. SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism
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Kory, Nora, Wyant, Gregory A., Prakash, Gyan, de Bos, Jelmi uit, Bottanelli, Francesca, Pacold, Michael E., Chan, Sze Ham, Lewis, Caroline A., Wang, Tim, Keys, Heather R., Guo, Yang Eric, and Sabatini, David M.
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- 2018
7. Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors
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Rohde, Jason M., Brimacombe, Kyle R., Liu, Li, Pacold, Michael E., Yasgar, Adam, Cheff, Dorian M., Lee, Tobie D., Rai, Ganesha, Baljinnyam, Bolormaa, Li, Zhuyin, Simeonov, Anton, Hall, Matthew D., Shen, Min, Sabatini, David M., and Boxer, Matthew B.
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- 2018
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8. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase
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Ilic, Nina, Birsoy, Kıvanç, Aguirre, Andrew J., Kory, Nora, Pacold, Michael E., Singh, Shambhavi, Moody, Susan E., DeAngelo, Joseph D., Spardy, Nicole A., Freinkman, Elizaveta, Weir, Barbara A., Tsherniak, Aviad, Cowley, Glenn S., Root, David E., Asara, John M., Vazquez, Francisca, Widlund, Hans R., Sabatini, David M., and Hahn, William C.
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- 2017
9. Data from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Ngo, Bryan, primary, Kim, Eugenie, primary, Osorio-Vasquez, Victoria, primary, Doll, Sophia, primary, Bustraan, Sophia, primary, Liang, Roger J., primary, Luengo, Alba, primary, Davidson, Shawn M., primary, Ali, Ahmed, primary, Ferraro, Gino B., primary, Fischer, Grant M., primary, Eskandari, Roozbeh, primary, Kang, Diane S., primary, Ni, Jing, primary, Plasger, Ariana, primary, Rajasekhar, Vinagolu K., primary, Kastenhuber, Edward R., primary, Bacha, Sarah, primary, Sriram, Roshan K., primary, Stein, Benjamin D., primary, Bakhoum, Samuel F., primary, Snuderl, Matija, primary, Cotzia, Paolo, primary, Healey, John H., primary, Mainolfi, Nello, primary, Suri, Vipin, primary, Friedman, Adam, primary, Manfredi, Mark, primary, Sabatini, David M., primary, Jones, Drew R., primary, Yu, Min, primary, Zhao, Jean J., primary, Jain, Rakesh K., primary, Keshari, Kayvan R., primary, Davies, Michael A., primary, Vander Heiden, Matthew G., primary, Hernando, Eva, primary, Mann, Matthias, primary, Cantley, Lewis C., primary, and Pacold, Michael E., primary
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- 2023
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10. Supplementary Figures S1-S9, Supplementary Table S1 from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Ngo, Bryan, primary, Kim, Eugenie, primary, Osorio-Vasquez, Victoria, primary, Doll, Sophia, primary, Bustraan, Sophia, primary, Liang, Roger J., primary, Luengo, Alba, primary, Davidson, Shawn M., primary, Ali, Ahmed, primary, Ferraro, Gino B., primary, Fischer, Grant M., primary, Eskandari, Roozbeh, primary, Kang, Diane S., primary, Ni, Jing, primary, Plasger, Ariana, primary, Rajasekhar, Vinagolu K., primary, Kastenhuber, Edward R., primary, Bacha, Sarah, primary, Sriram, Roshan K., primary, Stein, Benjamin D., primary, Bakhoum, Samuel F., primary, Snuderl, Matija, primary, Cotzia, Paolo, primary, Healey, John H., primary, Mainolfi, Nello, primary, Suri, Vipin, primary, Friedman, Adam, primary, Manfredi, Mark, primary, Sabatini, David M., primary, Jones, Drew R., primary, Yu, Min, primary, Zhao, Jean J., primary, Jain, Rakesh K., primary, Keshari, Kayvan R., primary, Davies, Michael A., primary, Vander Heiden, Matthew G., primary, Hernando, Eva, primary, Mann, Matthias, primary, Cantley, Lewis C., primary, and Pacold, Michael E., primary
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- 2023
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11. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
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Saxton, Robert A., Knockenhauer, Kevin E., Wolfson, Rachel L., Chantranupong, Lynne, Pacold, Michael E., Wang, Tim, Schwartz, Thomas U., and Sabatini, David M.
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- 2016
12. The uninhibited pathway is not worth studying
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Pacold, Michael E.
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- 2020
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13. Resurrecting essential amino acid biosynthesis in mammalian cells
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Trolle, Julie, primary, McBee, Ross M, primary, Kaufman, Andrew, additional, Pinglay, Sudarshan, additional, Berger, Henri, additional, German, Sergei, additional, Liu, Liyuan, additional, Shen, Michael J, additional, Guo, Xinyi, additional, Martin, J Andrew, additional, Pacold, Michael E, additional, Jones, Drew R, additional, Boeke, Jef D, additional, and Wang, Harris H, additional
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- 2022
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14. Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities
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Karz, Alcida, primary, Dimitrova, Maya, additional, Kleffman, Kevin, additional, Alvarez‐Breckenridge, Christopher, additional, Atkins, Michael B., additional, Boire, Adrienne, additional, Bosenberg, Marcus, additional, Brastianos, Priscilla, additional, Cahill, Daniel P., additional, Chen, Qing, additional, Ferguson, Sherise, additional, Forsyth, Peter, additional, Glitza Oliva, Isabella C., additional, Goldberg, Sarah B., additional, Holmen, Sheri L., additional, Knisely, Jonathan P. S., additional, Merlino, Glenn, additional, Nguyen, Don X., additional, Pacold, Michael E., additional, Perez‐Guijarro, Eva, additional, Smalley, Keiran S. M., additional, Tawbi, Hussein A., additional, Wen, Patrick Y., additional, Davies, Michael A., additional, Kluger, Harriet M., additional, Mehnert, Janice M., additional, and Hernando, Eva, additional
- Published
- 2022
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15. Author response: Resurrecting essential amino acid biosynthesis in mammalian cells
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Trolle, Julie, primary, McBee, Ross M, primary, Kaufman, Andrew, additional, Pinglay, Sudarshan, additional, Berger, Henri, additional, German, Sergei, additional, Liu, Liyuan, additional, Shen, Michael J, additional, Guo, Xinyi, additional, Martin, J Andrew, additional, Pacold, Michael E, additional, Jones, Drew R, additional, Boeke, Jef D, additional, and Wang, Harris H, additional
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- 2022
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16. mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin
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Kang, Seong A., Pacold, Michael E., Cervantes, Christopher L., Lim, Daniel, Lou, Hua Jane, Ottina, Kathleen, Gray, Nathanael S., Turk, Benjamin E., Yaffe, Michael B., and Sabatini, David M.
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- 2013
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17. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
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Kim, Dohoon, Fiske, Brian P., Birsoy, Kivanc, Freinkman, Elizaveta, Kami, Kenjiro, Possemato, Richard L., Chudnovsky, Yakov, Pacold, Michael E., Chen, Walter W., Cantor, Jason R., Shelton, Laura M., Gui, Dan Y., Kwon, Manjae, Ramkissoon, Shakti H., Ligon, Keith L., Kang, Seong Woo, Snuderl, Matija, Heiden, Matthew G. Vander, and Sabatini, David M.
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Ischemia -- Physiological aspects ,Gliomas -- Physiological aspects ,Glycine -- Health aspects ,Cancer cells -- Health aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment (1-3). Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition., Many inborn disorders of amino acid metabolism lead to severe impairment of the developing nervous system, at least in part through toxic effects on neural stem cells (4,5). As brain [...]
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- 2015
18. Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery
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Karve, Shrirang, Werner, Michael E., Sukumar, Rohit, Cummings, Natalie D., Copp, Jonathan A., Wang, Edina C., Li, Chenxi, Sethi, Manish, Chen, Ronald C., Pacold, Michael E., and Wang, Andrew Z.
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- 2012
19. METABOLISM: Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
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Saxton, Robert A., Knockenhauer, Kevin E., Wolfson, Rachel L., Chantranupong, Lynne, Pacold, Michael E., Wang, Tim, Schwartz, Thomas U., and Sabatini, David M.
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- 2016
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20. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling
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Floyd, Scott R., Pacold, Michael E., Huang, Qiuying, Clarke, Scott M., Lam, Fred C., Cannell, Ian G., and Bryson, Bryan D.
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DNA repair -- Analysis ,Chromatin -- Analysis ,DNA binding proteins -- Analysis ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Isoform B of the chromatin-binding protein Brd4 acts to suppress DNA damage response signalling. Brd4 modulates response to DNA damage The detection and repair of damaged DNA is vital for cell survival and the maintenance of an intact genome, but aberrant DNA damage signalling can be a cause of cancer. Here Michael Yaffe and colleagues examine the role of chromatin structure change in the activation of the DNA damage response (DDR). They find that the B isoform of the chromatin binding protein, Brd4, acts to suppress DDR signalling. As it is bound to acetylated histones, this Brd4 isoform recruits the condensin II chromatin remodelling complex, which prevents relaxation of the chromatin necessary for binding by factors that recognize and repair DNA damage. In this way, this Brd4 isoform regulates the strength of the DDR through mechanisms distinct from known transcriptional interactions with the P-TEFb transcriptional complex. DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death.sup.1. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response.sup.2. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage., Author(s): Scott R. Floyd [sup.1] [sup.2] , Michael E. Pacold [sup.1] [sup.3] [sup.4] , Qiuying Huang [sup.1] , Scott M. Clarke [sup.1] , Fred C. Lam [sup.1] , Ian G. [...]
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- 2013
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21. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
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Possemato, Richard, Marks, Kevin M., Shaul, Yoav D., Pacold, Michael E., Kim, Dohoon, Birsoy, Kivanc, Sethumadhavan, Shalini, Woo, Hin-Koon, Jang, Hyun G., Jha, Abhishek K., Chen, Walter W., Barrett, Francesca G., Stransky, Nicolas, Tsun, Zhi-Yang, Cowley, Glenn S., Barretina, Jordi, Kalaany, Nada Y., Hsu, Peggy P., Ottina, Kathleen, Chan, Albert M., Yuan, Bingbing, Brachtel, Lev Elena F., Driggers, Edward M., and Sabatini, David M.
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Gene expression -- Research ,Cancer cells -- Physiological aspects -- Research ,Breast cancer -- Genetic aspects -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation (1,2). RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new [...]
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- 2011
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22. Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Ngo, Bryan, Kim, Eugenie, Osorio-Vasquez, Victoria, Doll, Sophia, Bustraan, Sophia, Liang, Roger J, Luengo, Alba, Davidson, Shawn M, Ali, Ahmed, Ferraro, Gino B, Fischer, Grant M, Eskandari, Roozbeh, Kang, Diane S, Ni, Jing, Plasger, Ariana, Rajasekhar, Vinagolu K, Kastenhuber, Edward R, Bacha, Sarah, Sriram, Roshan K, Stein, Benjamin D, Bakhoum, Samuel F, Snuderl, Matija, Cotzia, Paolo, Healey, John H, Mainolfi, Nello, Suri, Vipin, Friedman, Adam, Manfredi, Mark, Sabatini, David M, Jones, Drew R, Yu, Min, Zhao, Jean J, Jain, Rakesh K, Keshari, Kayvan R, Davies, Michael A, Vander Heiden, Matthew G, Hernando, Eva, Mann, Matthias, Cantley, Lewis C, Pacold, Michael E, Ngo, Bryan, Kim, Eugenie, Osorio-Vasquez, Victoria, Doll, Sophia, Bustraan, Sophia, Liang, Roger J, Luengo, Alba, Davidson, Shawn M, Ali, Ahmed, Ferraro, Gino B, Fischer, Grant M, Eskandari, Roozbeh, Kang, Diane S, Ni, Jing, Plasger, Ariana, Rajasekhar, Vinagolu K, Kastenhuber, Edward R, Bacha, Sarah, Sriram, Roshan K, Stein, Benjamin D, Bakhoum, Samuel F, Snuderl, Matija, Cotzia, Paolo, Healey, John H, Mainolfi, Nello, Suri, Vipin, Friedman, Adam, Manfredi, Mark, Sabatini, David M, Jones, Drew R, Yu, Min, Zhao, Jean J, Jain, Rakesh K, Keshari, Kayvan R, Davies, Michael A, Vander Heiden, Matthew G, Hernando, Eva, Mann, Matthias, Cantley, Lewis C, and Pacold, Michael E
- Abstract
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacological inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggests that PHGDH inhibitors may be useful in the treatment of brain metastasis.
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- 2020
23. SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism
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Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kory, Nora, Wyant, Gregory A., Prakash, Gyan, De Bos, Jelmi uit, Pacold, Michael E., Chan, Sze Ham, Lewis, Caroline A., Wang, Tim, Keys, Heather R., Sabatini, David M., Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kory, Nora, Wyant, Gregory A., Prakash, Gyan, De Bos, Jelmi uit, Pacold, Michael E., Chan, Sze Ham, Lewis, Caroline A., Wang, Tim, Keys, Heather R., and Sabatini, David M.
- Abstract
One-carbon metabolism generates the one-carbon units required to synthesize many critical metabolites, including nucleotides. The pathway has cytosolic and mitochondrial branches, and a key step is the entry, through an unknown mechanism, of serine into mitochondria, where it is converted into glycine and formate. In a CRISPR-based genetic screen in human cells for genes of the mitochondrial pathway, we found sideroflexin 1 (SFXN1), a multipass inner mitochondrial membrane protein of unclear function. Like cells missing mitochondrial components of one-carbon metabolism, those null for SFXN1 are defective in glycine and purine synthesis. Cells lacking SFXN1 and one of its four homologs, SFXN3, have more severe defects, including being auxotrophic for glycine. Purified SFXN1 transports serine in vitro. Thus, SFXN1 functions as a mitochondrial serine transporter in one-carbon metabolism., National Institutes of Health (U.S.) (Grant R01 CA103866), National Institutes of Health (U.S.) (Grant R01 CA129105), National Institutes of Health (U.S.) (Grant R37 AI47389), United States. Department of Defense (Grant W81XWH-07–0448)
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- 2020
24. Selective metabolic redundancy of Gpi1 allows for specific inhibition of inflammatory Th17 cells
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Wu, Lin, Hollinshead, Kate E.R., Hao, Yuhan, Au, Christy, Kroehling, Lina, Ng, Charles, Lin, Woan-Yu, Li, Dayi, Silva, Hernandez Moura, Shin, Jong, Lafaille, Juan J., Possemato, Richard, Pacold, Michael E., Papagiannakopoulos, Thales Y., Kimmelman, Alec C., Satija, Rahul, and Littman, Dan R.
- Abstract
Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1 . Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.
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- 2019
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25. Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer
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Banh, Robert S., primary, Biancur, Douglas E., additional, Yamamoto, Keisuke, additional, Sohn, Albert S.W., additional, Walters, Beth, additional, Kuljanin, Miljan, additional, Gikandi, Ajami, additional, Wang, Huamin, additional, Mancias, Joseph D., additional, Schneider, Robert J., additional, Pacold, Michael E., additional, and Kimmelman, Alec C., additional
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- 2020
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26. Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain
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Chantranupong, Lynne, primary, Saulnier, Jessica L, additional, Wang, Wengang, additional, Jones, Drew R, additional, Pacold, Michael E, additional, and Sabatini, Bernardo L, additional
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- 2020
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27. Author response: Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain
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Chantranupong, Lynne, primary, Saulnier, Jessica L, additional, Wang, Wengang, additional, Jones, Drew R, additional, Pacold, Michael E, additional, and Sabatini, Bernardo L, additional
- Published
- 2020
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28. Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Ngo, Bryan, primary, Kim, Eugenie, additional, Osorio-Vasquez, Victoria, additional, Doll, Sophia, additional, Bustraan, Sophia, additional, Liang, Roger J., additional, Luengo, Alba, additional, Davidson, Shawn M., additional, Ali, Ahmed, additional, Ferraro, Gino B., additional, Fischer, Grant M., additional, Eskandari, Roozbeh, additional, Kang, Diane S., additional, Ni, Jing, additional, Plasger, Ariana, additional, Rajasekhar, Vinagolu K., additional, Kastenhuber, Edward R., additional, Bacha, Sarah, additional, Sriram, Roshan K., additional, Stein, Benjamin D., additional, Bakhoum, Samuel F., additional, Snuderl, Matija, additional, Cotzia, Paolo, additional, Healey, John H., additional, Mainolfi, Nello, additional, Suri, Vipin, additional, Friedman, Adam, additional, Manfredi, Mark, additional, Sabatini, David M., additional, Jones, Drew R., additional, Yu, Min, additional, Zhao, Jean J., additional, Jain, Rakesh K., additional, Keshari, Kayvan R., additional, Davies, Michael A., additional, Vander Heiden, Matthew G., additional, Hernando, Eva, additional, Mann, Matthias, additional, Cantley, Lewis C., additional, and Pacold, Michael E., additional
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- 2020
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29. Abstract 5712: Nutrient scarcity confers breast cancer brain metastasis sensitivity to serine synthesis pathway inhibition
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Ngo, Bryan, primary, Kim, Eugenie, additional, Doll, Sophia, additional, Bustraan, Sophia, additional, Luengo, Alba, additional, Davidson, Shawn M., additional, Ali, Ahmed, additional, Ferraro, Gino, additional, Kang, Diane, additional, Ni, Jing, additional, Liang, Roger, additional, Plasger, Ariana, additional, Kastenhuber, Edward R., additional, Eskandari, Roozbeh, additional, Bacha, Sarah, additional, Sriram, Roshan, additional, Stein, Benjamin D., additional, Bakhoum, Samuel F., additional, Mullarky, Edouard, additional, Snuderl, Matija, additional, Mainolfi, Nello, additional, Suri, Vipin, additional, Friedman, Adam, additional, Manfredi, Mark, additional, Sabatini, David M., additional, Jones, Drew, additional, Yu, Min, additional, Zhao, Jean J., additional, Jain, Rakesh K., additional, Heiden, Matthew G. Vander, additional, Mann, Matthias, additional, Cantley, Lewis C., additional, and Pacold, Michael E., additional
- Published
- 2020
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30. Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy
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Wu, Lin, primary, Hollinshead, Kate E.R., additional, Hao, Yuhan, additional, Au, Christy, additional, Kroehling, Lina, additional, Ng, Charles, additional, Lin, Woan-Yu, additional, Li, Dayi, additional, Silva, Hernandez Moura, additional, Shin, Jong, additional, Lafaille, Juan J., additional, Possemato, Richard, additional, Pacold, Michael E., additional, Papagiannakopoulos, Thales, additional, Kimmelman, Alec C., additional, Satija, Rahul, additional, and Littman, Dan R., additional
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- 2020
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31. Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis
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Ngo, Bryan, primary, Kim, Eugenie, additional, Osorio-Vasquez, Victoria, additional, Doll, Sophia, additional, Bustraan, Sophia, additional, Luengo, Alba, additional, Davidson, Shawn M., additional, Ali, Ahmed, additional, Ferraro, Gino D., additional, Kang, Diane, additional, Ni, Jing, additional, Liang, Roger, additional, Plasger, Ariana, additional, Kastenhuber, Edward R., additional, Eskandari, Roozbeh, additional, Bacha, Sarah, additional, Siriam, Roshan K., additional, Bakhoum, Samuel F., additional, Mullarky, Edouard, additional, Snuderl, Matija, additional, Cotzia, Paolo, additional, Mainolfi, Nello, additional, Suri, Vipin, additional, Friedman, Adam, additional, Manfredi, Mark, additional, Sabatini, David M., additional, Jones, Drew, additional, Yu, Min, additional, Zhao, Jean J., additional, Jain, Rakesh K., additional, Vander Heiden, Matthew G., additional, Hernando, Eva, additional, Mann, Matthias, additional, Cantley, Lewis C., additional, and Pacold, Michael E., additional
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- 2020
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32. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma
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Pacold, Michael E., Suire, Sabine, Perisic, Olga, Lara-Gonzalez, Samuel, Davis, Colin T., Walker, Edward H., Hawkins, T. Phillip, Stephens, Len, Eccleston, John F., and Williams, Roger L.
- Subjects
Ras genes -- Physiological aspects ,Phosphoinositides -- Physiological aspects ,Binding sites (Biochemistry) -- Analysis ,Crystals -- Structure ,Protein kinases -- Analysis ,Biological sciences - Abstract
Results demonstrate that the Ras activation of phosphoinositide 3-kinase gamma is brought about by positioning Ras by a loop in the binding domain such that the enzyme binds to switch I and II regions of Ras. Data suggest that the same interactions may occurr in the alpha-form-Ras binding.
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- 2000
33. Niche-selective inhibition of pathogenic Th17 cells by targeting metabolic redundancy
- Author
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Wu, Lin, primary, Hollinshead, Kate E.R., additional, Hao, Yuhan, additional, Au, Christy, additional, Kroehling, Lina, additional, Ng, Charles, additional, Lin, Woan-Yu, additional, Li, Dayi, additional, Silva, Hernandez Moura, additional, Shin, Jong, additional, Lafaille, Juan J., additional, Possemato, Richard, additional, Pacold, Michael E., additional, Papagiannakopoulos, Thales, additional, Kimmelman, Alec C., additional, Satija, Rahul, additional, and Littman, Dan R., additional
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- 2019
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34. The NADP-linked glyceraldehyde-3-phosphate dehydrogenases of Anabaena variabilis and Synechocystis PCC 6803, which lack one of the cysteines found in the higher plant enzyme, are not reductively activated
- Author
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Pacold, Michael E., Stevens, Fred J., Li, Dong, and Anderson, Louise E.
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- 1995
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35. Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors
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Rohde, Jason M., primary, Brimacombe, Kyle R., additional, Liu, Li, additional, Pacold, Michael E., additional, Yasgar, Adam, additional, Cheff, Dorian M., additional, Lee, Tobie D., additional, Rai, Ganesha, additional, Baljinnyam, Bolormaa, additional, Li, Zhuyin, additional, Simeonov, Anton, additional, Hall, Matthew D., additional, Shen, Min, additional, Sabatini, David M., additional, and Boxer, Matthew B., additional
- Published
- 2018
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36. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
- Author
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Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kim, Dohoon, Fiske, Brian Prescott, Birsoy, Kivanc, Freinkman, Elizaveta, Possemato, Richard, Chudnovsky, Yakov, Pacold, Michael E, Chen, Walter W., Cantor, Jason R., Gui, Dan Yi, Kwon, ManJae, Kang, Seong Woo, Vander Heiden, Matthew G., Sabatini, David, Kami, Kenjiro, Shelton, Laura M., Ramkissoon, Shakti H., Ligon, Keith L., Snuderl, Matija, Pacold, Michael Edward, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kim, Dohoon, Fiske, Brian Prescott, Birsoy, Kivanc, Freinkman, Elizaveta, Possemato, Richard, Chudnovsky, Yakov, Pacold, Michael E, Chen, Walter W., Cantor, Jason R., Gui, Dan Yi, Kwon, ManJae, Kang, Seong Woo, Vander Heiden, Matthew G., Sabatini, David, Kami, Kenjiro, Shelton, Laura M., Ramkissoon, Shakti H., Ligon, Keith L., Snuderl, Matija, and Pacold, Michael Edward
- Abstract
Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment1, 2, 3. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition., American Brain Tumor Association (Basic Research Fellowship), Massachusetts Institute of Technology. School of Science (Fellowship in Cancer Research), Jane Coffin Childs Memorial Fund for Medical Research (Fellowship), Leukemia & Lymphoma Society of America (Fellowship), National Institutes of Health (U.S.) (Grants T32GM007287, K99 CA168940, R01CA168653, 5P30CA14051, CA103866, CA129105, and AI07389), American Cancer Society (Fellowship), American Brain Tumor Association (Discovery Grant), National Institute on Aging (Fellowship), Smith Family Foundation, Burroughs Wellcome Fund, Damon Runyon Cancer Research Foundation, Stern Family, United States. Dept. of Defense. Congressionally Directed Medical Research Programs (Discovery Award), David H. Koch Institute for Integrative Cancer Research at MIT, Alexander and Margaret Stewart Trust
- Published
- 2017
37. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
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Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Saxton, Robert Andrew, Wolfson, Rachel Laura, Chantranupong, Lynne, Wang, Tim, Schwartz, Thomas, Sabatini, David, Knockenhauer, Kevin Edward, Pacold, Michael E, Pacold, Michael Edward, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Saxton, Robert Andrew, Wolfson, Rachel Laura, Chantranupong, Lynne, Wang, Tim, Schwartz, Thomas, Sabatini, David, Knockenhauer, Kevin Edward, Pacold, Michael E, and Pacold, Michael Edward
- Abstract
Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway., United States. Department of Defense (W81XWH-07- 0448), Damon Runyon Cancer Research Foundation (DRG-112-12), National Institutes of Health (U.S.) (Predoctoral Training Grant T32GM007287), National Institutes of Health (U.S.) (Grants R01CA103866, AI47389, T32 GM007753, F30 CA189333, F31 CA180271, and F31 CA189437), United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208), Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Whitaker Health Sciences Fund Fellowship), Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12)
- Published
- 2017
38. Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition
- Author
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Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology), Koch Institute for Integrative Cancer Research at MIT, Shaul, Yoav, Kim, Dohoon, Pacold, Michael E, Chen, Walter W., Possemato, Richard, Reinhardt, Ferenc, Weinberg, Robert A, Yaffe, Michael B, Sabatini, David, Freinkman, Elizaveta, Comb, William C., Cantor, Jason R., Tam, Wai Leong, Thiru, Prathapan, Kanarek, Naama, Bierie, Brian, Pacold, Michael Edward, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology), Koch Institute for Integrative Cancer Research at MIT, Shaul, Yoav, Kim, Dohoon, Pacold, Michael E, Chen, Walter W., Possemato, Richard, Reinhardt, Ferenc, Weinberg, Robert A, Yaffe, Michael B, Sabatini, David, Freinkman, Elizaveta, Comb, William C., Cantor, Jason R., Tam, Wai Leong, Thiru, Prathapan, Kanarek, Naama, Bierie, Brian, and Pacold, Michael Edward
- Abstract
It is increasingly appreciated that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote cancer cell aggressiveness. Here, we analyzed metabolic gene expression in cancer cell lines and found that a set of high-grade carcinoma lines expressing mesenchymal markers share a unique 44 gene signature, designated the “mesenchymal metabolic signature” (MMS). A FACS-based shRNA screen identified several MMS genes as essential for the epithelial-mesenchymal transition (EMT), but not for cell proliferation. Dihydropyrimidine dehydrogenase (DPYD), a pyrimidine-degrading enzyme, was highly expressed upon EMT induction and was necessary for cells to acquire mesenchymal characteristics in vitro and for tumorigenic cells to extravasate into the mouse lung. This role of DPYD was mediated through its catalytic activity and enzymatic products, the dihydropyrimidines. Thus, we identify metabolic processes essential for the EMT, a program associated with the acquisition of metastatic and aggressive cancer cell traits., United States. National Institutes of Health (RO1 CA103866), United States. National Institutes of Health (AI047389), United States. National Institutes of Health (K99 CA168940), American Cancer Society (PF-12-099-01-TGB), American Cancer Society (PF-13-356-01-TBE), United States. Department of Defense (BC123066), United States. National Institutes of Health (CA112967), United States. National Institutes of Health (ES015339)
- Published
- 2017
39. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase
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Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kory, Nora, Pacold, Michael E, Sabatini, David, Ilic, Nina, Birsoy, Kıvanç, Aguirre, Andrew J., Singh, Shambhavi, Moody, Susan E., DeAngelo, Joseph D., Spardy, Nicole A., Freinkman, Elizaveta, Weir, Barbara A., Tsherniak, Aviad, Cowley, Glenn S., Root, David E., Asara, John M., Vazquez, Francisca, Widlund, Hans R., Hahn, William C., Pacold, Michael Edward, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kory, Nora, Pacold, Michael E, Sabatini, David, Ilic, Nina, Birsoy, Kıvanç, Aguirre, Andrew J., Singh, Shambhavi, Moody, Susan E., DeAngelo, Joseph D., Spardy, Nicole A., Freinkman, Elizaveta, Weir, Barbara A., Tsherniak, Aviad, Cowley, Glenn S., Root, David E., Asara, John M., Vazquez, Francisca, Widlund, Hans R., Hahn, William C., and Pacold, Michael Edward
- Abstract
Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene. Keyword: PIK3CA; 2OG; OGDH; TCA cycle; glycolysis, Damon Runyon Cancer Research Foundation (HHMI Fellowship)
- Published
- 2017
40. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
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Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Pacold, Michael E, Chan, Sze Ham, Lewis, Caroline, Swier, Lotteke J. Y. M., Chen, Walter W., Sullivan, Lucas Bryan, Fiske, Brian Prescott, Cho, Sung Won, Abu-Remaileh, Monther, Liu, Chieh Ming Jamin, Zhou, Minerva H., Koh, Min Jung, Chung, Haeyoon, Davidson, Shawn M, Luengo, Alba, Vander Heiden, Matthew G., Sabatini, David, Pacold, Michael Edward, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Pacold, Michael E, Chan, Sze Ham, Lewis, Caroline, Swier, Lotteke J. Y. M., Chen, Walter W., Sullivan, Lucas Bryan, Fiske, Brian Prescott, Cho, Sung Won, Abu-Remaileh, Monther, Liu, Chieh Ming Jamin, Zhou, Minerva H., Koh, Min Jung, Chung, Haeyoon, Davidson, Shawn M, Luengo, Alba, Vander Heiden, Matthew G., Sabatini, David, and Pacold, Michael Edward
- Abstract
Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, ratelimiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo., Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12), United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208), American Society for Radiation Oncology (Resident Seed Grant RA-2011-1), European Molecular Biology Organization (Long-Term Fellowship), National Institutes of Health (U.S.) (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389), United States. Department of Defense (W81XWH-14-PRCRP-IA), Alexander and Margaret Stewart Trust
- Published
- 2017
41. Erratum: Corrigendum: A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
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Pacold, Michael E, primary, Brimacombe, Kyle R, additional, Chan, Sze Ham, additional, Rohde, Jason M, additional, Lewis, Caroline A, additional, Swier, Lotteke J Y M, additional, Possemato, Richard, additional, Chen, Walter W, additional, Sullivan, Lucas B, additional, Fiske, Brian P, additional, Cho, Steve, additional, Freinkman, Elizaveta, additional, Birsoy, Kıvanç, additional, Abu, Monther-Remaileh, additional, Shaul, Yoav D, additional, Liu, Chieh Min, additional, Zhou, Minerva, additional, Koh, Min Jung, additional, Chung, Haeyoon, additional, Davidson, Shawn M, additional, Luengo, Alba, additional, Wang, Amy Q, additional, Xu, Xin, additional, Yasgar, Adam, additional, Liu, Li, additional, Rai, Ganesha, additional, Westover, Kenneth D, additional, Heiden, Matthew G Vander, additional, Shen, Min, additional, Gray, Nathanael S, additional, Boxer, Matthew B, additional, and Sabatini, David M, additional
- Published
- 2016
- Full Text
- View/download PDF
42. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
- Author
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Pacold, Michael E, primary, Brimacombe, Kyle R, additional, Chan, Sze Ham, additional, Rohde, Jason M, additional, Lewis, Caroline A, additional, Swier, Lotteke J Y M, additional, Possemato, Richard, additional, Chen, Walter W, additional, Sullivan, Lucas B, additional, Fiske, Brian P, additional, Cho, Steve, additional, Freinkman, Elizaveta, additional, Birsoy, Kıvanç, additional, Abu-Remaileh, Monther, additional, Shaul, Yoav D, additional, Liu, Chieh Min, additional, Zhou, Minerva, additional, Koh, Min Jung, additional, Chung, Haeyoon, additional, Davidson, Shawn M, additional, Luengo, Alba, additional, Wang, Amy Q, additional, Xu, Xin, additional, Yasgar, Adam, additional, Liu, Li, additional, Rai, Ganesha, additional, Westover, Kenneth D, additional, Vander Heiden, Matthew G, additional, Shen, Min, additional, Gray, Nathanael S, additional, Boxer, Matthew B, additional, and Sabatini, David M, additional
- Published
- 2016
- Full Text
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43. Abstract PR10: Serine biosynthesis from glucose regulates folate availability
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Lewis, Caroline A., primary, Fiske, Brian P., additional, Pacold, Michael E., additional, Hosios, Aaron M., additional, Mattaini, Katherine R., additional, Sabatini, David M., additional, and Heiden, Matthew G. Vander, additional
- Published
- 2016
- Full Text
- View/download PDF
44. Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites
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Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Wang, Tim, Zhang, Feng, Carr, Steven A., Lander, Eric S., Regev, Aviv, Schwartz, Schraga, Mumbach, Maxwell R., Jovanovic, Marko, Maciag, Karolina, Bushkin, G. Guy, Mertins, Philipp, Ter-Ovanesyan, Dmitry, Habib, Naomi, Cacchiarelli, Davide, Sanjana, Neville E., Freinkman, Elizaveta, Pacold, Michael E., Satija, Rahul, Hacohen, Nir, Mikkelsen, Tarjei Sigurd, 1978, Carr, Steven A, Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Wang, Tim, Zhang, Feng, Carr, Steven A., Lander, Eric S., Regev, Aviv, Schwartz, Schraga, Mumbach, Maxwell R., Jovanovic, Marko, Maciag, Karolina, Bushkin, G. Guy, Mertins, Philipp, Ter-Ovanesyan, Dmitry, Habib, Naomi, Cacchiarelli, Davide, Sanjana, Neville E., Freinkman, Elizaveta, Pacold, Michael E., Satija, Rahul, Hacohen, Nir, Mikkelsen, Tarjei Sigurd, 1978, Carr, Steven A, and Lander, Eric Steven
- Abstract
N6-methyladenosine (m6A) is a common modification of mRNA with potential roles in fine-tuning the RNA life cycle. Here, we identify a dense network of proteins interacting with METTL3, a component of the methyltransferase complex, and show that three of them (WTAP, METTL14, and KIAA1429) are required for methylation. Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps and their classification into WTAP-dependent and -independent sites. WTAP-dependent sites are located at internal positions in transcripts, topologically static across a variety of systems we surveyed, and inversely correlated with mRNA stability, consistent with a role in establishing “basal” degradation rates. WTAP-independent sites form at the first transcribed base as part of the cap structure and are present at thousands of sites, forming a previously unappreciated layer of transcriptome complexity. Our data shed light on the proteomic and transcriptional underpinnings of this RNA modification., National Human Genome Research Institute (U.S.). Centers of Excellence in Genomic Science (P50 HG006193), National Human Genome Research Institute (U.S.) (U54 HG003067), National Institutes of Health (U.S.) (Pioneer Award)
- Published
- 2015
45. mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin
- Author
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Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kang, Seong A., Pacold, Michael E., Cervantes, Christopher L., Lim, Daniel Cham-Chin, Ottina, Kathleen, Yaffe, Michael B., Sabatini, David M., Lou, Hua Jane, Gray, Nathanael S., Turk, Benjamin E., Pacold, Michael Edward, Yaffe, Michael B, Sabatini, David, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Kang, Seong A., Pacold, Michael E., Cervantes, Christopher L., Lim, Daniel Cham-Chin, Ottina, Kathleen, Yaffe, Michael B., Sabatini, David M., Lou, Hua Jane, Gray, Nathanael S., Turk, Benjamin E., Pacold, Michael Edward, Yaffe, Michael B, and Sabatini, David
- Abstract
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals., National Institutes of Health (U.S.) (Grant CA103866), National Institutes of Health (U.S.) (Grant AI047389), National Institutes of Health (U.S.) (Grant ES015339), National Institutes of Health (U.S.) (Grant GM59281), National Institutes of Health (U.S.) (Grant CA112967), United States. Dept. of Defense (Grant W81XWH-07-0448), W. M. Keck Foundation, LAM Foundation, American Cancer Society (Fellowship), LAM Foundation (Fellowship), Damon Runyon Cancer Research Foundation (Fellowship), United States. Dept. of Defense. Breast Cancer Research Program (Fellowship)
- Published
- 2014
46. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling
- Author
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Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Floyd, Scott R., Pacold, Michael E., Huang, Qiuying, Clarke, Scott M., Lam, Fred Chiu-Lai, Cannell, Ian Gordon, Bryson, Bryan D., Rameseder, Jonathan, Lee, Michael J., Blake, Emily J., Fydrych, Anna, Ho, Richard, Greenberger, Benjamin Aaron, Chen, Grace, Maffa, Amanda D., Del Rosario, Amanda M., White, Forest M., Yaffe, Michael B., Sabatini, David M., Root, David E., Carpenter, Anne E., Hahn, William C., Chen, Clark C., Bradner, James E., Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Floyd, Scott R., Pacold, Michael E., Huang, Qiuying, Clarke, Scott M., Lam, Fred Chiu-Lai, Cannell, Ian Gordon, Bryson, Bryan D., Rameseder, Jonathan, Lee, Michael J., Blake, Emily J., Fydrych, Anna, Ho, Richard, Greenberger, Benjamin Aaron, Chen, Grace, Maffa, Amanda D., Del Rosario, Amanda M., White, Forest M., Yaffe, Michael B., Sabatini, David M., Root, David E., Carpenter, Anne E., Hahn, William C., Chen, Clark C., and Bradner, James E.
- Abstract
DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage., David H. Koch Institute for Integrative Cancer Research at MIT, National Institutes of Health (U.S.) (National Institute of Environmental Health Sciences Core Grant P30CA14051), National Institutes of Health (U.S.) (National Institute of Environmental Health Sciences Core Grant ES-002109), R01-ES15339, 1-U54-CA112967-04, R21-NS063917, SPARC Grant, American Board of Radiology (Holman Pathway Research Resident Seed Grant), American Society for Radiation Oncology (Junior Faculty Research Training Award)
- Published
- 2014
47. Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition
- Author
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Shaul, Yoav D., primary, Freinkman, Elizaveta, additional, Comb, William C., additional, Cantor, Jason R., additional, Tam, Wai Leong, additional, Thiru, Prathapan, additional, Kim, Dohoon, additional, Kanarek, Naama, additional, Pacold, Michael E., additional, Chen, Walter W., additional, Bierie, Brian, additional, Possemato, Richard, additional, Reinhardt, Ferenc, additional, Weinberg, Robert A., additional, Yaffe, Michael B., additional, and Sabatini, David M., additional
- Published
- 2014
- Full Text
- View/download PDF
48. Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites
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Schwartz, Schraga, primary, Mumbach, Maxwell R., additional, Jovanovic, Marko, additional, Wang, Tim, additional, Maciag, Karolina, additional, Bushkin, G. Guy, additional, Mertins, Philipp, additional, Ter-Ovanesyan, Dmitry, additional, Habib, Naomi, additional, Cacchiarelli, Davide, additional, Sanjana, Neville E., additional, Freinkman, Elizaveta, additional, Pacold, Michael E., additional, Satija, Rahul, additional, Mikkelsen, Tarjei S., additional, Hacohen, Nir, additional, Zhang, Feng, additional, Carr, Steven A., additional, Lander, Eric S., additional, and Regev, Aviv, additional
- Published
- 2014
- Full Text
- View/download PDF
49. Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor
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Lim, Sang Min, primary, Westover, Kenneth D., additional, Ficarro, Scott B., additional, Harrison, Rane A., additional, Choi, Hwan Geun, additional, Pacold, Michael E., additional, Carrasco, Martin, additional, Hunter, John, additional, Kim, Nam Doo, additional, Xie, Ting, additional, Sim, Taebo, additional, Jänne, Pasi A., additional, Meyerson, Matthew, additional, Marto, Jarrod A., additional, Engen, John R., additional, and Gray, Nathanael S., additional
- Published
- 2013
- Full Text
- View/download PDF
50. Slow Self-Activation Enhances The Potency of Viridin Prodrugs
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Blois, Joseph, primary, Yuan, Hushan, additional, Smith, Adam, additional, Pacold, Michael E., additional, Weissleder, Ralph, additional, Cantley, Lewis C., additional, and Josephson, Lee, additional
- Published
- 2008
- Full Text
- View/download PDF
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