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4. Uridine-derived ribose fuels glucose-restricted pancreatic cancer

Author

Nwosu, Zeribe C, Ward, Matthew H, Sajjakulnukit, Peter, Poudel, Pawan, Ragulan, Chanthirika, Kasperek, Steven, Radyk, Megan, Sutton, Damien, Menjivar, Rosa E, Andren, Anthony, Apiz-Saab, Juan J, Tolstyka, Zachary, Brown, Kristee, Lee, Ho-Joon, Dzierozynski, Lindsey N, He, Xi, PS, Hari, Ugras, Julia, Nyamundanda, Gift, Zhang, Li, Halbrook, Christopher J, Carpenter, Eileen S, Shi, Jiaqi, Shriver, Leah P, Patti, Gary J, Muir, Alexander, Pasca di Magliano, Marina, Sadanandam, Anguraj, and Lyssiotis, Costas A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Nutrition, Rare Diseases, Pancreatic Cancer, Diabetes, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Animals, Mice, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Ribose, Tumor Microenvironment, Uridine, Glucose, Cell Division, Cell Line, Tumor, MAP Kinase Signaling System, Uridine Phosphorylase, Humans, General Science & Technology
Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Published
2023

7. A metabolomic signature of the APOE2 allele

Author

Sebastiani, Paola, Song, Zeyuan, Ellis, Dylan, Tian, Qu, Schwaiger-Haber, Michaela, Stancliffe, Ethan, Lustgarten, Michael S, Funk, Cory C, Baloni, Priyanka, Yao, Cong-Hui, Joshi, Shakchhi, Marron, Megan M, Gurinovich, Anastasia, Li, Mengze, Leshchyk, Anastasia, Xiang, Qingyan, Andersen, Stacy L, Feitosa, Mary F, Ukraintseva, Svetlana, Soerensen, Mette, Fiehn, Oliver, Ordovas, Jose M, Haigis, Marcia, Monti, Stefano, Barzilai, Nir, Milman, Sofiya, Ferrucci, Luigi, Rappaport, Noa, Patti, Gary J, and Perls, Thomas T

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Genetics, Aging, Aged, 80 and over, Humans, Apolipoprotein E2, Polymorphism, Genetic, Alleles, Longitudinal Studies, Apolipoproteins E, Apolipoprotein E, Longevity, Metabolomics, Lipid metabolism, Clinical sciences
Abstract

With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR

Published
2023

8. Metabolite signatures of chronological age, aging, survival, and longevity

Author

Sebastiani, Paola, Monti, Stefano, Lustgarten, Michael S., Song, Zeyuan, Ellis, Dylan, Tian, Qu, Schwaiger-Haber, Michaela, Stancliffe, Ethan, Leshchyk, Anastasia, Short, Meghan I., Ardisson Korat, Andres V., Gurinovich, Anastasia, Karagiannis, Tanya, Li, Mengze, Lords, Hannah J., Xiang, Qingyan, Marron, Megan M., Bae, Harold, Feitosa, Mary F., Wojczynski, Mary K., O’Connell, Jeffrey R., Montasser, May E., Schupf, Nicole, Arbeev, Konstantin, Yashin, Anatoliy, Schork, Nicholas, Christensen, Kaare, Andersen, Stacy L., Ferrucci, Luigi, Rappaport, Noa, Perls, Thomas T., and Patti, Gary J.

Published
2024
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12. Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

Author

Acosta, Maria T., Adam, Margaret, Adams, David R., Alvarez, Raquel L., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Chinn, Ivan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Sessions Cole, F., Colley, Heather A., Cope, Heidi, Corner, Brian, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Dell’Angelica, Esteban C., Dickson, Patricia, Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Ezell, Kimberly, Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Goddard, Page C., Godfrey, Rena A., Golden-Grant, Katie, Grajewski, Alana, Hadley, Don, Hahn, Sihoun, Halley, Meghan C., Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Karaviti, Lefkothea, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Kozuira, Mary, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, AudreyStephannie, Mahoney, Rachel, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Lawrence Merritt, J., Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Mulvihill, John, Nakano-Okuno, Mariko, Nelson, Stanley F., Neumann, Serena, Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Carl Pallais, J., Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Potocki, Lorraine, Pusey Swerdzewski, Barbara N., Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Ron Scott, C., Seto, Elaine, Shashi, Vandana, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Kathleen, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tarakad, Arjun, Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Wallace, Stephanie, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Hubshman, Monika Weisz, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zhang, Zhe, Zuchner, Stephan, Legro, Nicole R., Bowman, Angela, Ugur, Berrak, Jackstadt, Madelyn M., Shriver, Leah P., Patti, Gary J., Zhang, Bo, Feng, Wenjia, McAdow, Anthony R., Goddard, Pagé, Jensen, Tanner, Fresard, Laure, Alvarez, Raquel, McCormack, Colleen, Holt, James M., Worthey, Elizabeth A., Montgomery, Stephen B., Postlethwait, John, De Camilli, Pietro, and Solnica-Krezel, Lila

Published
2024
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17. Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion.

Author

Ke, Wenfan, Saba, James A, Yao, Cong-Hui, Hilzendeger, Michael A, Drangowska-Way, Anna, Joshi, Chintan, Mony, Vinod K, Benjamin, Shawna B, Zhang, Sisi, Locasale, Jason, Patti, Gary J, Lewis, Nathan, and O'Rourke, Eyleen J

Abstract

The gut microbiota metabolizes drugs and alters their efficacy and toxicity. Diet alters drugs, the metabolism of the microbiota, and the host. However, whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. Here we show that dietary thymidine and serine enhance 5-fluoro 2'deoxyuridine (FUdR) toxicity in C. elegans through different microbial mechanisms. Thymidine promotes microbial conversion of the prodrug FUdR into toxic 5-fluorouridine-5'-monophosphate (FUMP), leading to enhanced host death associated with mitochondrial RNA and DNA depletion, and lethal activation of autophagy. By contrast, serine does not alter FUdR metabolism. Instead, serine alters E. coli's 1C-metabolism, reduces the provision of nucleotides to the host, and exacerbates DNA toxicity and host death without mitochondrial RNA or DNA depletion; moreover, autophagy promotes survival in this condition. This work implies that diet-microbe interactions can alter the host response to drugs without altering the drug or the host.

Published
2020

18. Leveraging insights into cancer metabolism—a symposium report

Author

Cable, Jennifer, Finley, Lydia, Tu, Benjamin P, Patti, Gary J, Oliver, Trudy G, Vardhana, Santosha, Mana, Miyeko, Ericksen, Russell, Khare, Sanika, DeBerardinis, Ralph, Stockwell, Brent R, Edinger, Aimee, Haigis, Marcia, and Kaelin, William

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Cell Transformation, Neoplastic, Congresses as Topic, Energy Metabolism, Humans, Metabolic Networks and Pathways, Neoplasms, New York City, Research Report, cancer, cell signaling, ferroptosis, micropinocytosis, metabolism, General Science & Technology
Abstract

Tumor cells have devised unique metabolic strategies to garner enough nutrients to sustain continuous growth and cell division. Oncogenic mutations may alter metabolic pathways to unlock new sources of energy, and cells take the advantage of various scavenging pathways to ingest material from their environment. These changes in metabolism result in a metabolic profile that, in addition to providing the building blocks for macromolecules, can also influence cell signaling pathways to promote tumor initiation and progression. Understanding what pathways tumor cells use to synthesize the materials necessary to support metabolic growth can pave the way for new cancer therapeutics. Potential strategies include depriving tumors of the materials needed to grow or targeting pathways involved in dependencies that arise by virtue of their altered metabolis.

Published
2020

21. International Ring Trial of a High Resolution Targeted Metabolomics and Lipidomics Platform for Serum and Plasma Analysis

Author

Thompson, J Will, Adams, Kendra J, Adamski, Jerzy, Asad, Yasmin, Borts, David, Bowden, John A, Byram, Gregory, Dang, Viet, Dunn, Warwick B, Fernandez, Facundo, Fiehn, Oliver, Gaul, David A, Hühmer, Andreas FR, Kalli, Anastasia, Koal, Therese, Koeniger, Stormy, Mandal, Rupasri, Meier, Florian, Naser, Fuad J, O’Neil, Donna, Pal, Akos, Patti, Gary J, Pham-Tuan, Hai, Prehn, Cornelia, Raynaud, Florence I, Shen, Tong, Southam, Andrew D, St. John-Williams, Lisa, Sulek, Karolina, Vasilopoulou, Catherine G, Viant, Mark, Winder, Catherine L, Wishart, David, Zhang, Lun, Zheng, Jiamin, and Moseley, M Arthur

Subjects
Amino Acids, Analysis of Variance, Animals, Biogenic Amines, Blood Chemical Analysis, Chromatography, High Pressure Liquid, Data Aggregation, Female, Humans, Limit of Detection, Lipidomics, Lipids, Male, Mass Spectrometry, Metabolome, Metabolomics, Mice, Rats, Reproducibility of Results, Analytical Chemistry, Other Chemical Sciences
Abstract

A challenge facing metabolomics in the analysis of large human cohorts is the cross-laboratory comparability of quantitative metabolomics measurements. In this study, 14 laboratories analyzed various blood specimens using a common experimental protocol provided with the Biocrates AbsoluteIDQ p400HR kit, to quantify up to 408 metabolites. The specimens included human plasma and serum from male and female donors, mouse and rat plasma, as well as NIST SRM 1950 reference plasma. The metabolite classes covered range from polar (e.g., amino acids and biogenic amines) to nonpolar (e.g., diacyl- and triacyl-glycerols), and they span 11 common metabolite classes. The manuscript describes a strict system suitability testing (SST) criteria used to evaluate each laboratory's readiness to perform the assay, and provides the SST Skyline documents for public dissemination. The study found approximately 250 metabolites were routinely quantified in the sample types tested, using Orbitrap instruments. Interlaboratory variance for the NIST SRM-1950 has a median of 10% for amino acids, 24% for biogenic amines, 38% for acylcarnitines, 25% for glycerolipids, 23% for glycerophospholipids, 16% for cholesteryl esters, 15% for sphingolipids, and 9% for hexoses. Comparing to consensus values for NIST SRM-1950, nearly 80% of comparable analytes demonstrated bias of

Published
2019

22. Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State

Author

Magtanong, Leslie, Ko, Pin-Joe, To, Milton, Cao, Jennifer Yinuo, Forcina, Giovanni C, Tarangelo, Amy, Ward, Carl C, Cho, Kevin, Patti, Gary J, Nomura, Daniel K, Olzmann, James A, and Dixon, Scott J

Subjects
1.1 Normal biological development and functioning, Underpinning research, Animals, Arachidonic Acid, Cell Line, Cell Membrane, Coenzyme A Ligases, Fatty Acids, Monounsaturated, Ferroptosis, Lipid Droplets, Lipids, Mice, Oxidation-Reduction, Phospholipid Hydroperoxide Glutathione Peroxidase, Reactive Oxygen Species, GPX4, MUFAs, cell death, ferroptosis, iron, lipid ROS, lipid droplet, lipotoxicity, oleate
Abstract

The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.

Published
2019

23. Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment

Author

Sponagel, Jasmin, Jones, Jill K., Frankfater, Cheryl, Zhang, Shanshan, Tung, Olivia, Cho, Kevin, Tinkum, Kelsey L., Gass, Hannah, Nunez, Elena, Spitz, Douglas R., Chinnaiyan, Prakash, Schaefer, Jacob, Patti, Gary J., Graham, Maya S., Mauguen, Audrey, Grkovski, Milan, Dunphy, Mark P., Krebs, Simone, Luo, Jingqin, Rubin, Joshua B., and Ippolito, Joseph E.

Published
2022
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25. MYC sensitises cells to apoptosis by driving energetic demand

Author

Edwards-Hicks, Joy, Su, Huizhong, Mangolini, Maurizio, Yoneten, Kubra K., Wills, Jimi, Rodriguez-Blanco, Giovanny, Young, Christine, Cho, Kevin, Barker, Heather, Muir, Morwenna, Guerrieri, Ania Naila, Li, Xue-Feng, White, Rachel, Manasterski, Piotr, Mandrou, Elena, Wills, Karen, Chen, Jingyu, Abraham, Emily, Sateri, Kianoosh, Qian, Bin-Zhi, Bankhead, Peter, Arends, Mark, Gammoh, Noor, von Kriegsheim, Alex, Patti, Gary J., Sims, Andrew H., Acosta, Juan Carlos, Brunton, Valerie, Kranc, Kamil R., Christophorou, Maria, Pearce, Erika L., Ringshausen, Ingo, and Finch, Andrew J.

Published
2022
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26. Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity

Author

Petersen, Max C., primary, Smith, Gordon I., additional, Palacios, Hector H., additional, Farabi, Sarah S., additional, Yoshino, Mihoko, additional, Yoshino, Jun, additional, Cho, Kevin, additional, Davila-Roman, Victor G., additional, Shankaran, Mahalakshmi, additional, Barve, Ruteja A., additional, Yu, Jinsheng, additional, Stern, Jennifer H., additional, Patterson, Bruce W., additional, Hellerstein, Marc K., additional, Shulman, Gerald I., additional, Patti, Gary J., additional, and Klein, Samuel, additional

Published
2024
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31. Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis

Author

Harrison, Gregory A., Wang, Erin R., Cho, Kevin, Mreyoud, Yassin, Sarkar, Souvik, Almqvist, Fredrik, Patti, Gary J., Stallings, Christina L., Harrison, Gregory A., Wang, Erin R., Cho, Kevin, Mreyoud, Yassin, Sarkar, Souvik, Almqvist, Fredrik, Patti, Gary J., and Stallings, Christina L.

Abstract

Of the approximately 10 million cases of Mycobacterium tuberculosis (Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for the growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor. IMPORTANCE Isoniazid (INH) is a critical frontline antibiotic to treat Mycobacterium tuberculosis (Mtb) infections. INH efficacy is limited by its suboptimal penetration of the Mtb-containing lesion and by the prevalence of clinical INH resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence o

Published
2024
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34. Abstract PR10: Uridine-to-ribose axis supports glucose-restricted pancreatic cancer

Author

Nwosu, Zeribe C., primary, Ward, Matthew H., additional, Sajjakulnukit, Peter, additional, Poudel, Pawan, additional, Ragulan, Chanthirika, additional, Kasperek, Steven, additional, Radyk, Megan, additional, Sutton, Damien, additional, Menjivar, Rosa E., additional, Andren, Anthony, additional, Apiz-Saab, Juan J., additional, Tolstyka, Zachary, additional, Brown, Kristee, additional, Lee, Ho-Joon, additional, Dzierozynski, Lindsey, additional, He, Xi, additional, Ps, Hari, additional, Ugras, Julia, additional, Nyamundanda, Gift, additional, Zhang, Li, additional, Halbrook, Christopher J., additional, Carpenter, Eileen, additional, Shi, Jiaqi, additional, Shriver, Leah P., additional, Patti, Gary J., additional, Muir, Alexander, additional, di Magliano, Marina Pasca, additional, Sadanandam, Anguraj, additional, and Lyssiotis, Costas A., additional

Published
2024
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39. Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis.

Author

Ivanisevic, Julijana, Elias, Darlene, Deguchi, Hiroshi, Averell, Patricia M, Kurczy, Michael, Johnson, Caroline H, Tautenhahn, Ralf, Zhu, Zhengjiang, Watrous, Jeramie, Jain, Mohit, Griffin, John, Patti, Gary J, and Siuzdak, Gary

Subjects
Humans, Oxygen, Lactic Acid, Blood Glucose, Amino Acids, Adult, Female, Male, Metabolomics
Abstract

The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (

Published
2015

40. Metabolism Links Bacterial Biofilms and Colon Carcinogenesis

Author

Johnson, Caroline H, Dejea, Christine M, Edler, David, Hoang, Linh T, Santidrian, Antonio F, Felding, Brunhilde H, Ivanisevic, Julijana, Cho, Kevin, Wick, Elizabeth C, Hechenbleikner, Elizabeth M, Uritboonthai, Winnie, Goetz, Laura, Casero, Robert A, Pardoll, Drew M, White, James R, Patti, Gary J, Sears, Cynthia L, and Siuzdak, Gary

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Medical Biochemistry and Metabolomics, Oncology and Carcinogenesis, Digestive Diseases, Cancer, Colo-Rectal Cancer, 2.1 Biological and endogenous factors, Aetiology, Bacteria, Bacterial Physiological Phenomena, Biofilms, Colonic Neoplasms, Female, Humans, Male, Spermine, Biochemistry and Cell Biology, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Bacterial biofilms in the colon alter the host tissue microenvironment. A role for biofilms in colon cancer metabolism has been suggested but to date has not been evaluated. Using metabolomics, we investigated the metabolic influence that microbial biofilms have on colon tissues and the related occurrence of cancer. Patient-matched colon cancers and histologically normal tissues, with or without biofilms, were examined. We show the upregulation of polyamine metabolites in tissues from cancer hosts with significant enhancement of N(1), N(12)-diacetylspermine in both biofilm-positive cancer and normal tissues. Antibiotic treatment, which cleared biofilms, decreased N(1), N(12)-diacetylspermine levels to those seen in biofilm-negative tissues, indicating that host cancer and bacterial biofilm structures contribute to the polyamine metabolite pool. These results show that colonic mucosal biofilms alter the cancer metabolome to produce a regulator of cellular proliferation and colon cancer growth potentially affecting cancer development and progression.

Published
2015

43. Interactive XCMS Online: Simplifying Advanced Metabolomic Data Processing and Subsequent Statistical Analyses

Author

Gowda, Harsha, Ivanisevic, Julijana, Johnson, Caroline H, Kurczy, Michael E, Benton, H Paul, Rinehart, Duane, Nguyen, Thomas, Ray, Jayashree, Kuehl, Jennifer, Arevalo, Bernardo, Westenskow, Peter D, Wang, Junhua, Arkin, Adam P, Deutschbauer, Adam M, Patti, Gary J, and Siuzdak, Gary

Subjects
Blood, Data Interpretation, Statistical, Databases, Factual, Desulfovibrio, Female, Humans, Internet, Lymphoma, Male, Mass Spectrometry, Meta-Analysis as Topic, Metabolomics, Multivariate Analysis, Principal Component Analysis, Software, User-Computer Interface, Analytical Chemistry, Other Chemical Sciences
Abstract

XCMS Online (xcmsonline.scripps.edu) is a cloud-based informatic platform designed to process and visualize mass-spectrometry-based, untargeted metabolomic data. Initially, the platform was developed for two-group comparisons to match the independent, "control" versus "disease" experimental design. Here, we introduce an enhanced XCMS Online interface that enables users to perform dependent (paired) two-group comparisons, meta-analysis, and multigroup comparisons, with comprehensive statistical output and interactive visualization tools. Newly incorporated statistical tests cover a wide array of univariate analyses. Multigroup comparison allows for the identification of differentially expressed metabolite features across multiple classes of data while higher order meta-analysis facilitates the identification of shared metabolic patterns across multiple two-group comparisons. Given the complexity of these data sets, we have developed an interactive platform where users can monitor the statistical output of univariate (cloud plots) and multivariate (PCA plots) data analysis in real time by adjusting the threshold and range of various parameters. On the interactive cloud plot, metabolite features can be filtered out by their significance level (p-value), fold change, mass-to-charge ratio, retention time, and intensity. The variation pattern of each feature can be visualized on both extracted-ion chromatograms and box plots. The interactive principal component analysis includes scores, loadings, and scree plots that can be adjusted depending on scaling criteria. The utility of XCMS functionalities is demonstrated through the metabolomic analysis of bacterial stress response and the comparison of lymphoblastic leukemia cell lines.

Published
2014

46. Table S3 from Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins

Author

Schab, Angela M., primary, Greenwade, Molly M., primary, Stock, Elizabeth, primary, Lomonosova, Elena, primary, Cho, Kevin, primary, Grither, Whitney R., primary, Noia, Hollie, primary, Wilke, Daniel, primary, Mullen, Mary M., primary, Hagemann, Andrea R., primary, Hagemann, Ian S., primary, Thaker, Premal H., primary, Kuroki, Lindsay M., primary, McCourt, Carolyn K., primary, Khabele, Dineo, primary, Powell, Matthew A., primary, Mutch, David G., primary, Zhao, Peinan, primary, Shriver, Leah P., primary, Patti, Gary J., primary, Longmore, Gregory D., primary, and Fuh, Katherine C., primary

Published
2023
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47. Figure S2 from Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins

Author

Schab, Angela M., primary, Greenwade, Molly M., primary, Stock, Elizabeth, primary, Lomonosova, Elena, primary, Cho, Kevin, primary, Grither, Whitney R., primary, Noia, Hollie, primary, Wilke, Daniel, primary, Mullen, Mary M., primary, Hagemann, Andrea R., primary, Hagemann, Ian S., primary, Thaker, Premal H., primary, Kuroki, Lindsay M., primary, McCourt, Carolyn K., primary, Khabele, Dineo, primary, Powell, Matthew A., primary, Mutch, David G., primary, Zhao, Peinan, primary, Shriver, Leah P., primary, Patti, Gary J., primary, Longmore, Gregory D., primary, and Fuh, Katherine C., primary

Published
2023
Full Text
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48. Supplementary Methods from Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins

Author

Schab, Angela M., primary, Greenwade, Molly M., primary, Stock, Elizabeth, primary, Lomonosova, Elena, primary, Cho, Kevin, primary, Grither, Whitney R., primary, Noia, Hollie, primary, Wilke, Daniel, primary, Mullen, Mary M., primary, Hagemann, Andrea R., primary, Hagemann, Ian S., primary, Thaker, Premal H., primary, Kuroki, Lindsay M., primary, McCourt, Carolyn K., primary, Khabele, Dineo, primary, Powell, Matthew A., primary, Mutch, David G., primary, Zhao, Peinan, primary, Shriver, Leah P., primary, Patti, Gary J., primary, Longmore, Gregory D., primary, and Fuh, Katherine C., primary

Published
2023
Full Text
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49. Data from Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins

Author

Schab, Angela M., primary, Greenwade, Molly M., primary, Stock, Elizabeth, primary, Lomonosova, Elena, primary, Cho, Kevin, primary, Grither, Whitney R., primary, Noia, Hollie, primary, Wilke, Daniel, primary, Mullen, Mary M., primary, Hagemann, Andrea R., primary, Hagemann, Ian S., primary, Thaker, Premal H., primary, Kuroki, Lindsay M., primary, McCourt, Carolyn K., primary, Khabele, Dineo, primary, Powell, Matthew A., primary, Mutch, David G., primary, Zhao, Peinan, primary, Shriver, Leah P., primary, Patti, Gary J., primary, Longmore, Gregory D., primary, and Fuh, Katherine C., primary

Published
2023
Full Text
View/download PDF

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