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1. Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors

Author

Chen, Jian Jenny, Vincent, Melanie Y., Shepard, Dale, Peereboom, David, Mahalingam, Devalingam, Battiste, James, Patel, Manish R., Juric, Dejan, Wen, Patrick Y., Bullock, Andrea, Selfridge, Jennifer Eva, Pant, Shubham, Liu, Joyce, Li, Wendy, Fyfe, Susanne, Wang, Suming, Zota, Victor, Mahoney, James, Watnick, Randolph S., Cieslewicz, Michael, and Watnick, Jing

Published
2024
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4. EYA2 Tyrosine Phosphatase Inhibition Reduces MYC and Prevents Medulloblastoma Progression

Author

Wolin, Arthur R, primary, Vincent, Melanie Y, additional, Hotz, Taylor, additional, Purdy, Stephen C, additional, Rosenbaum, Sheera R, additional, Hughes, Connor J, additional, Hsu, Jessica Y, additional, Oliphant, Michael U J, additional, Armstrong, Brock, additional, Wessells, Veronica, additional, Varella-Garcia, Marileila, additional, Galbraith, Matthew D, additional, Pierce, Angela, additional, Wang, Dong, additional, Venkataraman, Sujatha, additional, Danis, Etienne, additional, Veo, Bethany, additional, Serkova, Natalie, additional, Espinosa, Joaquin M, additional, Gustafson, Daniel L, additional, Vibhakar, Rajeev, additional, and Ford, Heide L, additional

Published
2023
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5. Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation

Author

Vartuli, Rebecca L., Zhou, Hengbo, Zhang, Lingdi, Powers, Rani K., Klarquist, Jared, Rudra, Pratyaydipta, Vincent, Melanie Y., Ghosh, Debashis, Costello, James C., Kedl, Ross M., Slansky, Jill E., Zhao, Rui, and Ford, Heide L.

Subjects
Immune response regulation -- Health aspects, Breast tumors -- Development and progression -- Genetic aspects, Membrane proteins -- Physiological aspects -- Health aspects, Transcriptional coactivators -- Physiological aspects -- Health aspects, Health care industry
Abstract

Eya proteins are critical developmental regulators that are highly expressed in embryogenesis but downregulated after development. Amplification and/or re-expression of Eyas occurs in many tumor types. In breast cancer, Eyas regulate tumor progression by acting as transcriptional cofactors and tyrosine phosphatases. Intriguingly, Eyas harbor a separate threonine (Thr) phosphatase activity, which was previously implicated in innate immunity. Here we describe what we believe to be a novel role for Eya3 in mediating triple-negative breast cancer-associated immune suppression. Eya3 loss decreases tumor growth in immune-competent mice and is associated with increased numbers of infiltrated [CD8.sup.+] T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased [CD8.sup.+] T cell signature. Our data uncover a role for Eya3 in mediating tumor-associated immune suppression, and suggest that its inhibition may enhance checkpoint therapies., Introduction The eyes absent family of proteins (Eyas 1-4) are crucial regulators of embryogenesis, contributing to the development of diverse tissues such as the ear (1, 2), eye (3), craniofacial [...]

Published
2018
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6. Data from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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7. Supplementary Figure 1 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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8. Supplementary Figure 4 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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9. Supplementary Figure 3 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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10. Supplementary Figure 6 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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11. Supplementary Figure 7 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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12. Supplementary Figure 2 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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13. Supplementary Figure 5 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, primary, Zhang, Lingdi, primary, Hotz, Taylor, primary, Vincent, Melanie Y., primary, Blevins, Melanie A., primary, Jansson, Anna E., primary, Kuan, John Wee Liang, primary, Ng, Elizabeth Yihui, primary, Yeo, Yee Khoon, primary, Baburajendran, Nithya, primary, Lin, Grace, primary, Hung, Alvin W., primary, Joy, Joma, primary, Patnaik, Samarjit, primary, Marugan, Juan, primary, Rudra, Pratyaydipta, primary, Ghosh, Debashis, primary, Hill, Jeffrey, primary, Keller, Thomas H., primary, Zhao, Rui, primary, Ford, Heide L., primary, and Kang, CongBao, primary

Published
2023
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14. Figure S6 from SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program

Author

Oliphant, Michael U.J., primary, Vincent, Melanie Y., primary, Galbraith, Matthew D., primary, Pandey, Ahwan, primary, Zaberezhnyy, Vadym, primary, Rudra, Pratyaydipta, primary, Johnson, Katherine R., primary, Costello, James C., primary, Ghosh, Debashis, primary, DeGregori, James, primary, Espinosa, Joaquin M., primary, and Ford, Heide L., primary

Published
2023
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15. Table S1 from SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program

Author

Oliphant, Michael U.J., primary, Vincent, Melanie Y., primary, Galbraith, Matthew D., primary, Pandey, Ahwan, primary, Zaberezhnyy, Vadym, primary, Rudra, Pratyaydipta, primary, Johnson, Katherine R., primary, Costello, James C., primary, Ghosh, Debashis, primary, DeGregori, James, primary, Espinosa, Joaquin M., primary, and Ford, Heide L., primary

Published
2023
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16. Data from SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program

Author

Oliphant, Michael U.J., primary, Vincent, Melanie Y., primary, Galbraith, Matthew D., primary, Pandey, Ahwan, primary, Zaberezhnyy, Vadym, primary, Rudra, Pratyaydipta, primary, Johnson, Katherine R., primary, Costello, James C., primary, Ghosh, Debashis, primary, DeGregori, James, primary, Espinosa, Joaquin M., primary, and Ford, Heide L., primary

Published
2023
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20. Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells

Author

Anantharajan, Jothi, primary, Zhou, Hengbo, additional, Zhang, Lingdi, additional, Hotz, Taylor, additional, Vincent, Melanie Y., additional, Blevins, Melanie A., additional, Jansson, Anna E., additional, Kuan, John Wee Liang, additional, Ng, Elizabeth Yihui, additional, Yeo, Yee Khoon, additional, Baburajendran, Nithya, additional, Lin, Grace, additional, Hung, Alvin W., additional, Joy, Joma, additional, Patnaik, Samarjit, additional, Marugan, Juan, additional, Rudra, Pratyaydipta, additional, Ghosh, Debashis, additional, Hill, Jeffrey, additional, Keller, Thomas H., additional, Zhao, Rui, additional, Ford, Heide L., additional, and Kang, CongBao, additional

Published
2019
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21. SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program

Author

Oliphant, Michael U.J., primary, Vincent, Melanie Y., additional, Galbraith, Matthew D., additional, Pandey, Ahwan, additional, Zaberezhnyy, Vadym, additional, Rudra, Pratyaydipta, additional, Johnson, Katherine R., additional, Costello, James C., additional, Ghosh, Debashis, additional, DeGregori, James, additional, Espinosa, Joaquin M., additional, and Ford, Heide L., additional

Published
2019
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23. Hypoosmotic swelling modifies glutamate-glutamine cycle in the cerebral cortex and in astrocyte cultures

Author

Hyzinski-García, María C., Vincent, Melanie Y., Haskew-Layton, Renée E., Dohare, Preeti, Keller, Richard W., and Mongin, Alexander A.

Subjects
Cerebral Cortex, Male, Saline Solution, Hypertonic, Aspartic Acid, Dose-Response Relationship, Drug, Glutamine, Microdialysis, Glutamic Acid, Extracellular Fluid, Tritium, Models, Biological, Article, Rats, Rats, Sprague-Dawley, Animals, Newborn, Glutaminase, Glutamate-Ammonia Ligase, Astrocytes, Animals, Cells, Cultured, Chromatography, High Pressure Liquid
Abstract

In our previous work, we found that perfusion of the rat cerebral cortex with hypo-osmotic medium triggers massive release of the excitatory amino acid L-glutamate but decreases extracellular levels of L-glutamine (R. E. Haskew-Layton et al., PLoS ONE, 3: e3543). The release of glutamate was linked to activation of volume-regulated anion channels, whereas mechanism(s) responsible for alterations in extracellular glutamine remained unclear. When mannitol was added to the hypo-osmotic medium to reverse reductions in osmolarity, changes in microdialysate levels of glutamine were prevented, indicating an involvement of cellular swelling. As the main source of brain glutamine is astrocytic synthesis and export, we explored the impact of hypo-osmotic medium on glutamine synthesis and transport in rat primary astrocyte cultures. In astrocytes, a 40% reduction in medium osmolarity moderately stimulated the release of L-[(3) H]glutamine by ∼twofold and produced no changes in L-[(3) H]glutamine uptake. In comparison, hypo-osmotic medium stimulated the release of glutamate (traced with D-[(3) H]aspartate) by more than 20-fold. In whole-cell enzymatic assays, we discovered that hypo-osmotic medium caused a 20% inhibition of astrocytic conversion of L-[(3) H]glutamate into L-[(3) H]glutamine by glutamine synthetase. Using an HPLC assay, we further found a 35% reduction in intracellular levels of endogenous glutamine. Overall, our findings suggest that cellular swelling (i) inhibits astrocytic glutamine synthetase activity, and (ii) reduces substrate availability for this enzyme because of the activation of volume-regulated anion channels. These combined effects likely lead to reductions in astrocytic glutamine export in vivo and may partially explain occurrence of hyperexcitability and seizures in human hyponatremia.

Published
2011

26. A simple method for measuring intracellular activities of glutamine synthetase and glutaminase in glial cells.

Author

Mongin AA, Hyzinski-García MC, Vincent MY, and Keller RW Jr

Subjects
Animals, Astrocytes cytology, Diazooxonorleucine pharmacology, Glutamate-Ammonia Ligase antagonists & inhibitors, Glutamate-Ammonia Ligase genetics, Glutaminase antagonists & inhibitors, Glutaminase genetics, Methionine Sulfoximine pharmacology, Neuroglia metabolism, Rats, Rats, Sprague-Dawley, Astrocytes metabolism, Enzyme Assays methods, Glutamate-Ammonia Ligase metabolism, Glutaminase metabolism, Neuroglia enzymology
Abstract

Here we report and validate a simple method for measuring intracellular activities of glial glutamine synthetase (GS) and glutaminase (GLNase) in intact glial cells. These enzymes are responsible for glutamate and glutamine recycling in the brain, where glutamate and glutamine transport from the blood stream is strongly limited by the blood-brain barrier. The intracellular levels of glutamate and glutamine are dependent on activities of numerous enzymatic processes, including 1) cytosolic production of glutamine from glutamate by GS, 2) production of glutamate from glutamine by GLNase that is primarily localized between mitochondrial membranes, and 3) mitochondrial conversion of glutamate to the tricarboxylic cycle intermediate α-ketoglutarate in the reactions of oxidative deamination and transamination. We measured intracellular activities of GS and GLNase by quantifying enzymatic interconversions of L-[(3)H]glutamate and L-[(3)H]glutamine in cultured rat astrocytes. The intracellular substrate and the products of enzymatic reactions were separated in one step using commercially available anion exchange columns and quantified using a scintillation counter. The involvement of GS and GLNase in the conversion of (3)H-labeled substrates was verified using irreversible pharmacological inhibitors for each of the enzymes and additionally validated by measuring intracellular amino acid levels using an HPLC. Overall, this paper describes optimized conditions and pharmacological controls for measuring GS and GLNase activities in intact glial cells.

Published
2011
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