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1. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Author

Sweha, Stefan, Mota, Mateus, Pun, Matthew, Deogharkar, Akash, Chung, Chan, Tarapore, Rohinton, Ramage, Samuel, Chi, Andrew, Wen, Patrick, Arrillaga-Romany, Isabel, Batchelor, Tracy, Butowski, Nicholas, Sumrall, Ashley, Shonka, Nicole, Harrison, Rebecca, de Groot, John, Mehta, Minesh, Hall, Matthew, Daghistani, Doured, Cloughesy, Timothy, Ellingson, Benjamin, Beccaria, Kevin, Varlet, Pascale, Kim, Michelle, Umemura, Yoshie, Garton, Hugh, Franson, Andrea, Schwartz, Jonathan, Jain, Rajan, Kachman, Maureen, Baum, Heidi, Burant, Charles, Mottl, Sophie, Cartaxo, Rodrigo, John, Vishal, Messinger, Dana, Qin, Tingting, Peterson, Erik, Sajjakulnukit, Peter, Ravi, Karthik, Waugh, Alyssa, Walling, Dustin, Ding, Yujie, Xia, Ziyun, Schwendeman, Anna, Hawes, Debra, Yang, Fusheng, Judkins, Alexander, Wahl, Daniel, Lyssiotis, Costas, de la Nava, Daniel, Alonso, Marta, Eze, Augustine, Spitzer, Jasper, Schmidt, Susanne, Duchatel, Ryan, Dun, Matthew, Cain, Jason, Jiang, Li, Stopka, Sylwia, Baquer, Gerard, Regan, Michael, Filbin, Mariella, Agar, Nathalie, Zhao, Lili, Kumar-Sinha, Chandan, Mody, Rajen, Chinnaiyan, Arul, Kurokawa, Ryo, Pratt, Drew, Yadav, Viveka, Grill, Jacques, Kline, Cassie, Venneti, Sriram, Kawakibi, Abed, Ji, Sunjong, Resnick, Adam, Nazarian, Javad, Allen, Joshua, Odia, Yazmin, Gardner, Sharon, Koschmann, Carl, Mueller, Sabine, and Waszak, Sebastian

Subjects
Humans, Glioma, Brain Neoplasms, Histones, Treatment Outcome, Epigenesis, Genetic, Mutation
Abstract

UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Published
2023

4. Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

Author

Coy, Shannon, Wang, Shu, Stopka, Sylwia A., Lin, Jia-Ren, Yapp, Clarence, Ritch, Cecily C., Salhi, Lisa, Baker, Gregory J., Rashid, Rumana, Baquer, Gerard, Regan, Michael, Khadka, Prasidda, Cole, Kristina A., Hwang, Jaeho, Wen, Patrick Y., Bandopadhayay, Pratiti, Santi, Mariarita, De Raedt, Thomas, Ligon, Keith L., Agar, Nathalie Y. R., Sorger, Peter K., Touat, Mehdi, and Santagata, Sandro

Published
2022
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5. Spatial Profiling of Metals through Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging

Author

Stopka, Sylwia A., primary, Bodineau, Clément, additional, Baquer, Gerard, additional, Lin, Jia-Ren, additional, Hossain, Md Amin, additional, Regan, Michael S., additional, Ruiz, Daniela, additional, Fletcher, Stecia-Marie, additional, Pourquié, Olivier, additional, Lutsenko, Svetlana, additional, Payne, Connor N., additional, Agar, Jeffrey N., additional, Mazitschek, Ralph, additional, McDannold, Nathan J., additional, Sorger, Peter K., additional, Santagata, Sandro, additional, and Agar, Nathalie Y. R., additional

Published
2024
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6. The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.

Author

York, Elisa M., Miller, Anne, Stopka, Sylwia A., Martínez-François, Juan Ramón, Hossain, Md Amin, Baquer, Gerard, Regan, Michael S., Agar, Nathalie Y. R., and Yellen, Gary

Subjects
DENTATE gyrus, ALTERNATIVE fuels, BRAIN metabolism, GRANULE cells, CARBON metabolism, PYRUVATES, GLUTAMINE
Abstract

The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI-MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β-hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Table S4 from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Author

Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

Published
2023
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8. Supplementary Figures 1-15 from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Author

Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

Published
2023
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9. Supplementary Data S2 from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Author

Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

Published
2023
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10. Data from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Author

Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

Published
2023
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11. Rewiring of cortical glucose metabolism fuels human brain cancer growth

Author

Scott, Andrew J, primary, Mittal, Anjali, additional, Meghdadi, Baharan, additional, Palavalasa, Sravya, additional, Achreja, Abhinav, additional, O'Brien, Alexandra, additional, Kothari, Ayesha U, additional, Zhou, Weihua, additional, Xu, Jie, additional, Lin, Angelica, additional, Wilder-Romans, Kari, additional, Edwards, Donna M, additional, Wu, Zhe, additional, Feng, Jiane, additional, Andren, Anthony C, additional, Zhang, Li, additional, Tarnal, Vijay, additional, Redic, Kimberly A, additional, Qi, Nathan, additional, Fischer, Joshua, additional, Yang, Ethan, additional, Regan, Michael S, additional, Stopko, Sylwia A, additional, Baquer, Gerard, additional, Lawrence, Theodore S, additional, Venneti, Sriram, additional, Agar, Nathalie Y.R., additional, Lyssiotis, Costas A, additional, Al-Holou, Wajd N, additional, Nagrath, Deepak, additional, and Wahl, Daniel R, additional

Published
2023
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12. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Author

Venneti, Sriram, primary, Kawakibi, Abed Rahman, additional, Ji, Sunjong, additional, Waszak, Sebastian M., additional, Sweha, Stefan R., additional, Mota, Mateus, additional, Pun, Matthew, additional, Deogharkar, Akash, additional, Chung, Chan, additional, Tarapore, Rohinton S., additional, Ramage, Samuel, additional, Chi, Andrew, additional, Wen, Patrick Y., additional, Arrillaga-Romany, Isabel, additional, Batchelor, Tracy T., additional, Butowski, Nicholas A., additional, Sumrall, Ashley, additional, Shonka, Nicole, additional, Harrison, Rebecca A., additional, de Groot, John, additional, Mehta, Minesh, additional, Hall, Matthew D., additional, Daghistani, Doured, additional, Cloughesy, Timothy F., additional, Ellingson, Benjamin M., additional, Beccaria, Kevin, additional, Varlet, Pascale, additional, Kim, Michelle M., additional, Umemura, Yoshie, additional, Garton, Hugh, additional, Franson, Andrea, additional, Schwartz, Jonathan, additional, Jain, Rajan, additional, Kachman, Maureen, additional, Baum, Heidi, additional, Burant, Charles F., additional, Mottl, Sophie L., additional, Cartaxo, Rodrigo T., additional, John, Vishal, additional, Messinger, Dana, additional, Qin, Tingting, additional, Peterson, Erik, additional, Sajjakulnukit, Peter, additional, Ravi, Karthik, additional, Waugh, Alyssa, additional, Walling, Dustin, additional, Ding, Yujie, additional, Xia, Ziyun, additional, Schwendeman, Anna, additional, Hawes, Debra, additional, Yang, Fusheng, additional, Judkins, Alexander R., additional, Wahl, Daniel, additional, Lyssiotis, Costas A., additional, de la Nava, Daniel, additional, Alonso, Marta M., additional, Eze, Augustine, additional, Spitzer, Jasper, additional, Schmidt, Susanne V., additional, Duchatel, Ryan J., additional, Dun, Matthew D., additional, Cain, Jason E., additional, Jiang, Li, additional, Stopka, Sylwia A., additional, Baquer, Gerard, additional, Regan, Michael S., additional, Filbin, Mariella G., additional, Agar, Nathalie Y.R., additional, Zhao, Lili, additional, Kumar-Sinha, Chandan, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Kurokawa, Ryo, additional, Pratt, Drew, additional, Yadav, Viveka N., additional, Grill, Jacques, additional, Kline, Cassie, additional, Mueller, Sabine, additional, Resnick, Adam, additional, Nazarian, Javad, additional, Allen, Joshua E., additional, Odia, Yazmin, additional, Gardner, Sharon L., additional, and Koschmann, Carl, additional

Published
2023
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13. Chemical QuantArray: A Quantitative Tool for Mass Spectrometry Imaging

Author

Stopka, Sylwia A., primary, Ruiz, Daniela, additional, Baquer, Gerard, additional, Bodineau, Clément, additional, Hossain, Md Amin, additional, Pellens, Valentina T., additional, Regan, Michael S., additional, Pourquié, Olivier, additional, Haigis, Marcia C., additional, Bi, Wenya L., additional, Coy, Shannon M., additional, Santagata, Sandro, additional, Agar, Nathalie Y. R., additional, and Basu, Sankha S., additional

Published
2023
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15. WSD-0922, a novel brain-penetrant inhibitor of EGFR, promotes survival in glioblastoma mouse models

Author

Conage-Pough, Jason E, primary, Stopka, Sylwia A, additional, Oh, Ju-Hee, additional, Mladek, Ann C, additional, Burgenske, Danielle M, additional, Regan, Michael S, additional, Baquer, Gerard, additional, Decker, Paul A, additional, Carlson, Brett L, additional, Bakken, Katrina K, additional, Zhang, Jinqiang, additional, Liu, Lily, additional, Sun, Claire, additional, Mu, Zhihua, additional, Zhong, Wei, additional, Tran, Nhan L, additional, Elmquist, William F, additional, Agar, Nathalie Y R, additional, Sarkaria, Jann N, additional, and White, Forest M, additional

Published
2023
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16. Abstract 1156: GUK1 is a novel metabolic liability in oncogene-driven lung cancer

Author

Schneider, Jaime Laurel, primary, Kurmi, Kiran, additional, Dhiman, Ishita, additional, Colapietro, Roberta, additional, Joshi, Shakchhi, additional, Johnson, Christian, additional, Yoda, Satoshi, additional, Paulo, Joao, additional, Ruiz, Daniela, additional, Stopka, Sylwia, additional, Baquer, Gerard, additional, Lin, Jessica, additional, Haigis, Kevin, additional, Agar, Nathalie, additional, Gygi, Steven, additional, Hata, Aaron, additional, and Haigis, Marcia, additional

Published
2023
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18. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

Author

Wang, Lin, primary, Wang, Dan, additional, Sonzogni, Olmo, additional, Ke, Shizhong, additional, Wang, Qi, additional, Thavamani, Abhishek, additional, Batalini, Felipe, additional, Stopka, Sylwia A., additional, Regan, Michael S., additional, Vandal, Steven, additional, Tian, Shengya, additional, Pinto, Jocelin, additional, Cyr, Andrew M., additional, Bret-Mounet, Vanessa C., additional, Baquer, Gerard, additional, Eikesdal, Hans P., additional, Yuan, Min, additional, Asara, John M., additional, Heng, Yujing J., additional, Bai, Peter, additional, Agar, Nathalie Y.R., additional, and Wulf, Gerburg M., additional

Published
2022
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19. What are we imaging? Software tools and experimental strategies for annotation and identification of small molecules in mass spectrometry imaging.

Author

Baquer, Gerard, Sementé, Lluc, Mahamdi, Toufik, Correig, Xavier, Ràfols, Pere, and García‐Altares, María

Subjects
*MASS spectrometry, *SOFTWARE development tools, *SMALL molecules, *IDENTIFICATION, *ANNOTATIONS, *LIPIDOMICS
Abstract

Mass spectrometry imaging (MSI) has become a widespread analytical technique to perform nonlabeled spatial molecular identification. The Achilles' heel of MSI is the annotation and identification of molecular species due to intrinsic limitations of the technique (lack of chromatographic separation and the difficulty to apply tandem MS). Successful strategies to perform annotation and identification combine extra analytical steps, like using orthogonal analytical techniques to identify compounds; with algorithms that integrate the spectral and spatial information. In this review, we discuss different experimental strategies and bioinformatics tools to annotate and identify compounds in MSI experiments. We target strategies and tools for small molecule applications, such as lipidomics and metabolomics. First, we explain how sample preparation and the acquisition process influences annotation and identification, from sample preservation to the use of orthogonal techniques. Then, we review twelve software tools for annotation and identification in MSI. Finally, we offer perspectives on two current needs of the MSI community: the adaptation of guidelines for communicating confidence levels in identifications; and the creation of a standard format to store and exchange annotations and identifications in MSI. [ABSTRACT FROM AUTHOR]

Published
2023
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20. Oncometabolite d -2HG alters T cell metabolism to impair CD8 + T cell function

Author

Notarangelo, Giulia, primary, Spinelli, Jessica B., additional, Perez, Elizabeth M., additional, Baker, Gregory J., additional, Kurmi, Kiran, additional, Elia, Ilaria, additional, Stopka, Sylwia A., additional, Baquer, Gerard, additional, Lin, Jia-Ren, additional, Golby, Alexandra J., additional, Joshi, Shakchhi, additional, Baron, Heide F., additional, Drijvers, Jefte M., additional, Georgiev, Peter, additional, Ringel, Alison E., additional, Zaganjor, Elma, additional, McBrayer, Samuel K., additional, Sorger, Peter K., additional, Sharpe, Arlene H., additional, Wucherpfennig, Kai W., additional, Santagata, Sandro, additional, Agar, Nathalie Y. R., additional, Suvà, Mario L., additional, and Haigis, Marcia C., additional

Published
2022
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22. Supporting Information for SALDI-MS and SERS multimodal imaging: One nanostructured substrate to rule them both

Author

Iakab, Stefania-Alexandra, Baquer, Gerard, Lafuente, Marta, Pina, María Pilar, Ramírez, José Luis, Ràfols, Pere, Correig-Blanchar, Xavier, García-Altares, María, Iakab, Stefania-Alexandra, Baquer, Gerard, Lafuente, Marta, Pina, María Pilar, Ramírez, José Luis, Ràfols, Pere, Correig-Blanchar, Xavier, and García-Altares, María

Abstract

Comparison between SERS imaging, SALDI MSI, and multimodal imaging on AuBSi; physico-chemical characterization of the AuBSi substrate; AuBSi performance for SALDI-MSI and SERS imaging; coregistration strategy; and tentative annotation of bands (SERS) and ions (SALDI) detected from the same fingerprint sweat on AuBSi.

Published
2022

23. SALDI-MS and SERS multimodal imaging: One nanostructured substrate to rule them both

Author

Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, European Research Council, Universidad Rovira i Virgili, Iakab, Stefania-Alexandra, Baquer, Gerard, Lafuente, Marta, Pina, María Pilar, Ramírez, José Luis, Ràfols, Pere, Correig-Blanchar, Xavier, García-Altares, María, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, European Research Council, Universidad Rovira i Virgili, Iakab, Stefania-Alexandra, Baquer, Gerard, Lafuente, Marta, Pina, María Pilar, Ramírez, José Luis, Ràfols, Pere, Correig-Blanchar, Xavier, and García-Altares, María

Abstract

Imaging techniques based on mass spectrometry or spectroscopy methods inform in situ about the chemical composition of biological tissues or organisms, but they are sometimes limited by their specificity, sensitivity, or spatial resolution. Multimodal imaging addresses these limitations by combining several imaging modalities; however, measuring the same sample with the same preparation using multiple imaging techniques is still uncommon due to the incompatibility between substrates, sample preparation protocols, and data formats. We present a multimodal imaging approach that employs a gold-coated nanostructured silicon substrate to couple surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) and surface-enhanced Raman spectroscopy (SERS). Our approach integrates both imaging modalities by using the same substrate, sample preparation, and data analysis software on the same sample, allowing the coregistration of both images. We transferred molecules from clean fingertips and fingertips covered with plasticine modeling clay onto our nanostructure and analyzed their chemical composition and distribution by SALDI-MS and SERS. Multimodal analysis located the traces of plasticine on fingermarks and provided chemical information on the composition of the clay. Our multimodal approach effectively combines the advantages of mass spectrometry and vibrational spectroscopy with the signal enhancing abilities of our nanostructured substrate.

Published
2022

24. What are we imaging? Software tools and experimental strategies for annotation and identification of small molecules in mass spectrometry imaging

Author

Universitat Rovira i Virgili, Baquer, Gerard; Semente, Lluc; Mahamdi, Toufik; Correig, Xavier; Rafols, Pere; Garcia-Altares, Maria, Universitat Rovira i Virgili, and Baquer, Gerard; Semente, Lluc; Mahamdi, Toufik; Correig, Xavier; Rafols, Pere; Garcia-Altares, Maria

Abstract

Mass spectrometry imaging (MSI) has become a widespread analytical technique to perform nonlabeled spatial molecular identification. The Achilles' heel of MSI is the annotation and identification of molecular species due to intrinsic limitations of the technique (lack of chromatographic separation and the difficulty to apply tandem MS). Successful strategies to perform annotation and identification combine extra analytical steps, like using orthogonal analytical techniques to identify compounds; with algorithms that integrate the spectral and spatial information. In this review, we discuss different experimental strategies and bioinformatics tools to annotate and identify compounds in MSI experiments. We target strategies and tools for small molecule applications, such as lipidomics and metabolomics. First, we explain how sample preparation and the acquisition process influences annotation and identification, from sample preservation to the use of orthogonal techniques. Then, we review twelve software tools for annotation and identification in MSI. Finally, we offer perspectives on two current needs of the MSI community: the adaptation of guidelines for communicating confidence levels in identifications; and the creation of a standard format to store and exchange annotations and identifications in MSI.

Published
2022

26. WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models.

Author

Conage-Pough, Jason E, Stopka, Sylwia A, Oh, Ju-Hee, Mladek, Ann C, Burgenske, Danielle M, Regan, Michael S, Baquer, Gerard, Decker, Paul A, Carlson, Brett L, Bakken, Katrina K, Zhang, Jinqiang, Liu, Lily, Sun, Claire, Mu, Zhihua, Zhong, Wei, Tran, Nhan L, Elmquist, William F, Agar, Nathalie Y R, Sarkaria, Jann N, and White, Forest M

Published
2023
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28. Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function.

Author

Notarangelo, Giulia, Spinelli, Jessica B., Perez, Elizabeth M., Baker, Gregory J., Kurmi, Kiran, Elia, Ilaria, Stopka, Sylwia A., Baquer, Gerard, Lin, Jia-Ren, Golby, Alexandra J., Joshi, Shakchhi, Baron, Heide F., Drijvers, Jefte M., Georgiev, Peter, Ringel, Alison E., Zaganjor, Elma, McBrayer, Samuel K., Sorger, Peter K., Sharpe, Arlene H., and Wucherpfennig, Kai W.

Published
2022
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30. rMSIcleanup: an open-source tool for matrix-related peak annotation in mass spectrometry imaging and its application to silver-assisted laser desorption/ionization

Author

Universitat Rovira i Virgili, Baquer, Gerard; Semente, Lluc; Garcia-Altares, Maria; Lee, Young Jin; Chaurand, Pierre; Correig, Xavier; Rafols, Pere, Universitat Rovira i Virgili, and Baquer, Gerard; Semente, Lluc; Garcia-Altares, Maria; Lee, Young Jin; Chaurand, Pierre; Correig, Xavier; Rafols, Pere

Abstract

Mass spectrometry imaging (MSI) has become a mature, widespread analytical technique to perform non-targeted spatial metabolomics. However, the compounds used to promote desorption and ionization of the analyte during acquisition cause spectral interferences in the low mass range that hinder downstream data processing in metabolomics applications. Thus, it is advisable to annotate and remove matrix-related peaks to reduce the number of redundant and non-biologically-relevant variables in the dataset. We have developed rMSIcleanup, an open-source R package to annotate and remove signals from the matrix, according to the matrix chemical composition and the spatial distribution of its ions. To validate the annotation method, rMSIcleanup was challenged with several images acquired using silver-assisted laser desorption ionization MSI (AgLDI MSI). The algorithm was able to correctly classify m/z signals related to silver clusters. Visual exploration of the data using Principal Component Analysis (PCA) demonstrated that annotation and removal of matrix-related signals improved spectral data post-processing. The results highlight the need for including matrix-related peak annotation tools such as rMSIcleanup in MSI workflows.

Published
2020

31. rMSIcleanup: An open-source tool for matrix-related peak annotation in mass spectrometry imaging and its application to silver-assisted laser desorption/ionization

Author

Baquer, Gerard, Sementé, Lluc, García-Altares, María, Lee, Young Jin, Chaurand, Pierre, Correig, Xavier, and Ràfols, Pere

Subjects
0301 basic medicine, Matrix annotation, Analyte, Materials science, Computer science, Silver-assisted laser/desorption ionization, Overlapping-signal detection, Library and Information Sciences, 01 natural sciences, Mass spectrometry imaging, Matrix (chemical analysis), lcsh:Chemistry, 03 medical and health sciences, Annotation, Metabolomics, Ionization, Spatial metabolomics, Physical and Theoretical Chemistry, 030304 developmental biology, Data processing, 0303 health sciences, Spectral processing, lcsh:T58.5-58.64, business.industry, lcsh:Information technology, 010401 analytical chemistry, Analytical technique, Pattern recognition, Computer Graphics and Computer-Aided Design, Computer Science Applications, 0104 chemical sciences, 030104 developmental biology, lcsh:QD1-999, Principal component analysis, Artificial intelligence, Biological system, business, Research Article
Abstract

Mass spectrometry imaging (MSI) has become a mature, widespread analytical technique to perform non-targeted spatial metabolomics. However, the compounds used to promote desorption and ionization of the analyte during acquisition cause spectral interferences in the low mass range that hinder downstream data processing in metabolomics applications. Thus, it is advisable to annotate and remove matrix-related peaks to reduce the number of redundant and non-biologically-relevant variables in the dataset. We have developed rMSIcleanup, an open-source R package to annotate and remove matrix-related signals based on its chemical formula and the spatial distribution of its ions. To validate the annotation method, rMSIcleanup was challenged with several images acquired using silver-assisted laser desorption ionization MSI (AgLDI MSI). The algorithm was able to correctly classify m/z signals related to silver clusters. Visual exploration of the data using Principal Component Analysis (PCA) demonstrated that annotation and removal of matrix-related signals improved spectral data post-processing. The results highlight the need for including matrix-related peak annotation tools such as rMSIcleanup in MSI workflows.Resources availabilityThe R package presented in this publication is freely available under the terms of the GNU General Public License v3.0 at https://github.com/gbaquer/rMSIcleanup. The datasets used in the experiments can be accessed upon request to the corresponding author.

Published
2019
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33. DNA-PK inhibition shows differential radiosensitization in orthotopic GBM PDX models based on DDR pathway deficits.

Author

Dragojevic S, Smith EJ, Regan MS, Stopka SA, Baquer G, Xue Z, Zhang W, Connors MA, Kloeber JA, Hu Z, Bakken KK, Ott LL, Carlson BL, Burgenske DM, Decker PA, Tian S, Gupta SK, Laverty DJ, Eckel-Passow JE, Elmquist WF, Agar NYR, Nagel ZD, Sarkaria JN, and Callaghan CM

Abstract

Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi's) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi's is critical to avoid unnecessary increased risk of normal tissue toxicity. In this study we used GBM patient derived xenografts (PDXs) in orthotopic murine models to study the relationship between molecular features, pharmacokinetics, and the radiosensitizing potential of the DNA-PKi peposertib. We show that peposertib radiosensitizes established and PDX GBM lines in vitro at 300nM and above, with significant increase in radiosensitization by maintaining post-IR exposure for >12 hours. Radiosensitization by peposertib is mediated by catalytic inhibition of DNA-PK, and knock-down of DNA-PK by short hairpin RNA (shRNA) largely abolished the radiosensitizing effect. Peposertib decreased auto-phosphorylation of DNA-PKcs after IR in a dose-dependent manner with delay in resolution of γH2AX foci at 24 hours. The addition of peposertib to IR significantly increased survival in GBM120 orthotopic xenografts, but not in GBM10. There was no difference in plasma or average tumor concentrations of peposertib in the two cohorts. While the mechanism underpinning this discordant effect in vitro vs. in vivo is not clear, there was an association for greater sensitization in TP53 mutant lines. Transfection of a dominant-negative TP53 mutant in baseline TP53 wildtype GBM lines significantly delayed growth and decreased NHEJ efficiency (but not Homologous Recombination), after peposertib exposure.

Published
2024
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34. Investigative needle core biopsies for multi-omics in Glioblastoma.

Author

Yu KKH, Basu S, Baquer G, Ahn R, Gantchev J, Jindal S, Regan MS, Abou-Mrad Z, Prabhu MC, Williams MJ, D'Souza AD, Malinowski SW, Hopland K, Elhanati Y, Stopka SA, Stortchevoi A, He Z, Sun J, Chen Y, Espejo AB, Chow KH, Yerrum S, Kao PL, Kerrigan BP, Norberg L, Nielsen D, Puduvalli VK, Huse J, Beroukhim R, Kim YSB, Goswami S, Boire A, Frisken S, Cima MJ, Holdhoff M, Lucas CG, Bettegowda C, Levine SS, Bale TA, Brennan C, Reardon DA, Lang FF, Antonio Chiocca E, Ligon KL, White FM, Sharma P, Tabar V, and Agar NYR

Abstract

Glioblastoma (GBM) is a primary brain cancer with an abysmal prognosis and few effective therapies. The ability to investigate the tumor microenvironment before and during treatment would greatly enhance both understanding of disease response and progression, as well as the delivery and impact of therapeutics. Stereotactic biopsies are a routine surgical procedure performed primarily for diagnostic histopathologic purposes. The role of investigative biopsies - tissue sampling for the purpose of understanding tumor microenvironmental responses to treatment using integrated multi-modal molecular analyses ('Multi-omics") has yet to be defined. Secondly, it is unknown whether comparatively small tissue samples from brain biopsies can yield sufficient information with such methods. Here we adapt stereotactic needle core biopsy tissue in two separate patients. In the first patient with recurrent GBM we performed highly resolved multi-omics analysis methods including single cell RNA sequencing, spatial-transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics from biopsy tissue that was obtained from a single procedure. In a second patient we analyzed multi-regional core biopsies to decipher spatial and genomic variance. We also investigated the utility of stereotactic biopsies as a method for generating patient derived xenograft models in a separate patient cohort. Dataset integration across modalities showed good correspondence between spatial modalities, highlighted immune cell associated metabolic pathways and revealed poor correlation between RNA expression and the tumor MHC Class I immunopeptidome. In conclusion, stereotactic needle biopsy cores are of sufficient quality to generate multi-omics data, provide data rich insight into a patient's disease process and tumor immune microenvironment and can be of value in evaluating treatment responses., One Sentence Summary: Integrative multi-omics analysis of stereotactic needle core biopsies in glioblastoma.

Published
2023
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35. Rewiring of cortical glucose metabolism fuels human brain cancer growth.

Author

Scott AJ, Mittal A, Meghdadi B, Palavalasa S, Achreja A, O'Brien A, Kothari AU, Zhou W, Xu J, Lin A, Wilder-Romans K, Edwards DM, Wu Z, Feng J, Andren AC, Zhang L, Tarnal V, Redic KA, Qi N, Fischer J, Yang E, Regan MS, Stopka SA, Baquer G, Lawrence TS, Venneti S, Agar NYR, Lyssiotis CA, Al-Holou WN, Nagrath D, and Wahl DR

Abstract

The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13 C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth., Significance: This study is the first to directly measure biosynthetic flux in both glioma and cortical tissue in human brain cancer patients. Brain tumors rewire glucose carbon utilization away from oxidation and neurotransmitter production towards biosynthesis to fuel growth. Blocking these metabolic adaptations with dietary interventions slows brain cancer growth with minimal effects on cortical metabolism.

Published
2023
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36. Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.

Author

Miller A, York E, Stopka S, Martínez-François J, Hossain MA, Baquer G, Regan M, Agar N, and Yellen G

Abstract

Neuronal activity creates an intense energy demand that must be met by rapid metabolic responses. To investigate metabolic adaptations in the neuron-enriched dentate granule cell (DGC) layer within its native tissue environment, we employed murine acute hippocampal brain slices coupled with fast metabolite preservation, followed by mass spectrometry imaging (MALDI-MSI) to generate spatially resolved metabolomics and isotope tracing data. Here we show that membrane depolarization induces broad metabolic changes, including increased glycolytic activity in DGCs. Increased glucose metabolism in response to stimulation is accompanied by mobilization of endogenous inosine into pentose phosphates, via the action of purine nucleotide phosphorylase (PNP). The PNP reaction is an integral part of the neuronal response to stimulation, as inhibiting PNP leaves DGCs energetically impaired during recovery from strong activation. Performing MSI on brain slices bridges the gap between live cell physiology and the deep chemical analysis enabled by mass spectrometry.

Published
2023
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