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356 results on '"DeNicola, Gina"'

1. Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools

Author

Pezacki, Aidan T, Matier, Carson D, Gu, Xingxing, Kummelstedt, Eric, Bond, Sarah E, Torrente, Laura, Jordan-Sciutto, Kelly L, DeNicola, Gina M, Su, Timothy A, Brady, Donita C, and Chang, Christopher J

Subjects
Copper, Fluorescent Dyes, Glutathione, Imidazoles, Oncogenes, Oxidation-Reduction, activity-based sensing, fluorescent copper probe, oxidative stress, transition metal signaling, cancer metabolism
Abstract

Copper is an essential metal nutrient for life that often relies on redox cycling between Cu(I) and Cu(II) oxidation states to fulfill its physiological roles, but alterations in cellular redox status can lead to imbalances in copper homeostasis that contribute to cancer and other metalloplasias with metal-dependent disease vulnerabilities. Copper-responsive fluorescent probes offer powerful tools to study labile copper pools, but most of these reagents target Cu(I), with limited methods for monitoring Cu(II) owing to its potent fluorescence quenching properties. Here, we report an activity-based sensing strategy for turn-on, oxidation state-specific detection of Cu(II) through metal-directed acyl imidazole chemistry. Cu(II) binding to a metal and oxidation state-specific receptor that accommodates the harder Lewis acidity of Cu(II) relative to Cu(I) activates the pendant dye for reaction with proximal biological nucleophiles and concomitant metal ion release, thus avoiding fluorescence quenching. Copper-directed acyl imidazole 649 for Cu(II) (CD649.2) provides foundational information on the existence and regulation of labile Cu(II) pools, including identifying divalent metal transporter 1 (DMT1) as a Cu(II) importer, labile Cu(II) increases in response to oxidative stress induced by depleting total glutathione levels, and reciprocal increases in labile Cu(II) accompanied by decreases in labile Cu(I) induced by oncogenic mutations that promote oxidative stress.

Published
2022

2. Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.

Author

Ravichandran, Mirunalini, Hu, Jingjie, Cai, Charles, Ward, Nathan P, Venida, Anthony, Foakes, Callum, Kuljanin, Miljan, Yang, Annan, Hennessey, Connor J, Yang, Yang, Desousa, Brandon R, Rademaker, Gilles, Staes, Annelot AL, Cakir, Zeynep, Jain, Isha H, Aguirre, Andrew J, Mancias, Joseph D, Shen, Yin, DeNicola, Gina M, and Perera, Rushika M

Subjects
Digestive Diseases, Cancer, Genetics, Rare Diseases, Pancreatic Cancer, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, Generic health relevance, Humans, Biological Availability, Carcinoma, Pancreatic Ductal, Iron, Iron-Sulfur Proteins, Nuclear Receptor Coactivators, Pancreatic Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins p21(ras), Sulfur, Transcription Factors, Oncology and Carcinogenesis
Abstract

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition.SignificanceReduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.

Published
2022

3. Connecting copper and cancer: from transition metal signalling to metalloplasia

Author

Ge, Eva J, Bush, Ashley I, Casini, Angela, Cobine, Paul A, Cross, Justin R, DeNicola, Gina M, Dou, Q Ping, Franz, Katherine J, Gohil, Vishal M, Gupta, Sanjeev, Kaler, Stephen G, Lutsenko, Svetlana, Mittal, Vivek, Petris, Michael J, Polishchuk, Roman, Ralle, Martina, Schilsky, Michael L, Tonks, Nicholas K, Vahdat, Linda T, Van Aelst, Linda, Xi, Dan, Yuan, Peng, Brady, Donita C, and Chang, Christopher J

Subjects
2.1 Biological and endogenous factors, Aetiology, Cancer, Autophagy, Cell Proliferation, Copper, Humans, Neoplasms, Signal Transduction, Medical and Health Sciences, Oncology & Carcinogenesis
Abstract

Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.

Published
2022

4. Ferroptosis in health and disease

Author

Berndt, Carsten, Alborzinia, Hamed, Amen, Vera Skafar, Ayton, Scott, Barayeu, Uladzimir, Bartelt, Alexander, Bayir, Hülya, Bebber, Christina M., Birsoy, Kivanc, Böttcher, Jan P., Brabletz, Simone, Brabletz, Thomas, Brown, Ashley R., Brüne, Bernhard, Bulli, Giorgia, Bruneau, Alix, Chen, Quan, DeNicola, Gina M., Dick, Tobias P., Distéfano, Ayelén, Dixon, Scott J., Engler, Jan B., Esser-von Bieren, Julia, Fedorova, Maria, Friedmann Angeli, José Pedro, Friese, Manuel A., Fuhrmann, Dominic C., García-Sáez, Ana J., Garbowicz, Karolina, Götz, Magdalena, Gu, Wei, Hammerich, Linda, Hassannia, Behrouz, Jiang, Xuejun, Jeridi, Aicha, Kang, Yun Pyo, Kagan, Valerian E., Konrad, David B., Kotschi, Stefan, Lei, Peng, Le Tertre, Marlène, Lev, Sima, Liang, Deguang, Linkermann, Andreas, Lohr, Carolin, Lorenz, Svenja, Luedde, Tom, Methner, Axel, Michalke, Bernhard, Milton, Anna V., Min, Junxia, Mishima, Eikan, Müller, Sebastian, Motohashi, Hozumi, Muckenthaler, Martina U., Murakami, Shohei, Olzmann, James A., Pagnussat, Gabriela, Pan, Zijan, Papagiannakopoulos, Thales, Pedrera Puentes, Lohans, Pratt, Derek A., Proneth, Bettina, Ramsauer, Lukas, Rodriguez, Raphael, Saito, Yoshiro, Schmidt, Felix, Schmitt, Carina, Schulze, Almut, Schwab, Annemarie, Schwantes, Anna, Soula, Mariluz, Spitzlberger, Benedikt, Stockwell, Brent R., Thewes, Leonie, Thorn-Seshold, Oliver, Toyokuni, Shinya, Tonnus, Wulf, Trumpp, Andreas, Vandenabeele, Peter, Vanden Berghe, Tom, Venkataramani, Vivek, Vogel, Felix C.E., von Karstedt, Silvia, Wang, Fudi, Westermann, Frank, Wientjens, Chantal, Wilhelm, Christoph, Wölk, Michele, Wu, Katherine, Yang, Xin, Yu, Fan, Zou, Yilong, and Conrad, Marcus

Published
2024
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14. A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Author

Pezacki, Aidan T., Gonciarz, Ryan L., Toshitaka Okamura, Matier, Carson D., Torrente, Laura, Ke Cheng, Miller, Sophia G., Ralle, Martina, Ward, Nathan P., DeNicola, Gina M., Renslo, Adam R., and Chang, Christopher J.

Abstract

Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation-reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography

Author

Greenwood, Hannah E., primary, Edwards, Richard S., additional, Tyrrell, Will E., additional, Barber, Abigail R., additional, Baark, Friedrich, additional, Tanc, Muhammet, additional, Khalil, Eman, additional, Falzone, Aimee, additional, Ward, Nathan P., additional, DeBlasi, Janine M., additional, Torrente, Laura, additional, Pearce, David R., additional, Firth, George, additional, Smith, Lydia M., additional, Timmermand, Oskar Vilhelmsson, additional, Huebner, Ariana, additional, George, Madeleine E., additional, Swanton, Charles, additional, Hynds, Robert E., additional, DeNicola, Gina M., additional, and Witney, Timothy H., additional

Published
2023
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18. Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms of the pancreas

Author

Beato, Francisca, Reverón, Dayana, Dezsi, Kaleena B., Ortiz, Antonio, Johnson, Joseph O., Chen, Dung-Tsa, Ali, Karla, Yoder, Sean J., Jeong, Daniel, Malafa, Mokenge, Hodul, Pamela, Jiang, Kun, Centeno, Barbara A., Abdalah, Mahmoud A., Balasi, Jodi A., Tassielli, Alexandra F., Sarcar, Bhaswati, Teer, Jamie K., DeNicola, Gina M., Permuth, Jennifer B., and Fleming, Jason B.

Published
2021
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20. ASCT2 is the primary serine transporter in cancer cells

Author

Conger, Kelly O, primary, Chidley, Christopher, additional, Ozgurses, Mete Emir, additional, Zhao, Huiping, additional, Kim, Yumi, additional, Semina, Svetlana E, additional, Burns, Philippa A, additional, Rawat, Vipin, additional, Sheldon, Ryan, additional, Ben-Sahra, Issam, additional, Frasor, Jonna, additional, Sorger, Peter Karl, additional, DeNicola, Gina M, additional, and Coloff, Jonathan L, additional

Published
2023
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22. A PI3K gene expression signature predicts for recurrence in early‐stage non–small cell lung cancer treated with stereotactic body radiation therapy (SBRT)

Author

Sebastian, Nikhil T., primary, Webb, Amy, additional, Shilo, Konstantin, additional, Robb, Ryan, additional, Xu‐Welliver, Meng, additional, Haglund, Karl, additional, Brownstein, Jeremy, additional, DeNicola, Gina M., additional, Shen, Changxian, additional, and Williams, Terence M., additional

Published
2023
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23. Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion

Author

Harris, Isaac S., Endress, Jennifer E., Coloff, Jonathan L., Selfors, Laura M., McBrayer, Samuel K., Rosenbluth, Jennifer M., Takahashi, Nobuaki, Dhakal, Sabin, Koduri, Vidyasagar, Oser, Matthew G., Schauer, Nathan J., Doherty, Laura M., Hong, Andrew L., Kang, Yun Pyo, Younger, Scott T., Doench, John G., Hahn, William C., Buhrlage, Sara J., DeNicola, Gina M., Kaelin, William G., Jr., and Brugge, Joan S.

Published
2019
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24. Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy

Author

Rawat, Vipin, primary, DeLear, Patrick, additional, Prashanth, Prarthana, additional, Ozgurses, Mete Emir, additional, Tebeje, Anteneh, additional, Burns, Philippa A., additional, Conger, Kelly O., additional, Solís, Christopher, additional, Hasnain, Yasir, additional, Novikova, Anna, additional, Endress, Jennifer E., additional, González-Sánchez, Paloma, additional, Dong, Wentao, additional, Stephanopoulos, Greg, additional, DeNicola, Gina M., additional, Harris, Isaac S., additional, Sept, David, additional, Mason, Frank M., additional, and Coloff, Jonathan L., additional

Published
2023
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33. Supplementary Data from Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS–MAPK Pathway Inhibition in Pancreatic Cancer

Author

Ravichandran, Mirunalini, primary, Hu, Jingjie, primary, Cai, Charles, primary, Ward, Nathan P., primary, Venida, Anthony, primary, Foakes, Callum, primary, Kuljanin, Miljan, primary, Yang, Annan, primary, Hennessey, Connor J., primary, Yang, Yang, primary, Desousa, Brandon R., primary, Rademaker, Gilles, primary, Staes, Annelot A.L., primary, Cakir, Zeynep, primary, Jain, Isha H., primary, Aguirre, Andrew J., primary, Mancias, Joseph D., primary, Shen, Yin, primary, DeNicola, Gina M., primary, and Perera, Rushika M., primary

Published
2023
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34. Abstract 6029: Multi-omic landscape of squamous cell lung cancer

Author

Stewart, Paul, primary, Lui, Ashley, additional, Welsh, Eric, additional, Ercan, Dalia, additional, Rubio, Vanessa, additional, Ackerman, Hayley, additional, Li, Guohui, additional, Fang, Bin, additional, Eschrich, Steven, additional, Koomen, John, additional, Flores, Elsa, additional, Haura, Eric, additional, and DeNicola, Gina, additional

Published
2023
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35. Data from Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS–MAPK Pathway Inhibition in Pancreatic Cancer

Author

Ravichandran, Mirunalini, primary, Hu, Jingjie, primary, Cai, Charles, primary, Ward, Nathan P., primary, Venida, Anthony, primary, Foakes, Callum, primary, Kuljanin, Miljan, primary, Yang, Annan, primary, Hennessey, Connor J., primary, Yang, Yang, primary, Desousa, Brandon R., primary, Rademaker, Gilles, primary, Staes, Annelot A.L., primary, Cakir, Zeynep, primary, Jain, Isha H., primary, Aguirre, Andrew J., primary, Mancias, Joseph D., primary, Shen, Yin, primary, DeNicola, Gina M., primary, and Perera, Rushika M., primary

Published
2023
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36. Supplementary Figure from Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS–MAPK Pathway Inhibition in Pancreatic Cancer

Author

Ravichandran, Mirunalini, primary, Hu, Jingjie, primary, Cai, Charles, primary, Ward, Nathan P., primary, Venida, Anthony, primary, Foakes, Callum, primary, Kuljanin, Miljan, primary, Yang, Annan, primary, Hennessey, Connor J., primary, Yang, Yang, primary, Desousa, Brandon R., primary, Rademaker, Gilles, primary, Staes, Annelot A.L., primary, Cakir, Zeynep, primary, Jain, Isha H., primary, Aguirre, Andrew J., primary, Mancias, Joseph D., primary, Shen, Yin, primary, DeNicola, Gina M., primary, and Perera, Rushika M., primary

Published
2023
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38. Figure S7 from Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer

Author

Humpton, Timothy J., primary, Alagesan, Brinda, primary, DeNicola, Gina M., primary, Lu, Dan, primary, Yordanov, Georgi N., primary, Leonhardt, Carl S., primary, Yao, Melissa A., primary, Alagesan, Priya, primary, Zaatari, Maya N., primary, Park, Youngkyu, primary, Skepper, Jeremy N., primary, Macleod, Kay F., primary, Perez-Mancera, Pedro A., primary, Murphy, Michael P., primary, Evan, Gerard I., primary, Vousden, Karen H., primary, and Tuveson, David A., primary

Published
2023
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40. Data from Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer

Author

Humpton, Timothy J., primary, Alagesan, Brinda, primary, DeNicola, Gina M., primary, Lu, Dan, primary, Yordanov, Georgi N., primary, Leonhardt, Carl S., primary, Yao, Melissa A., primary, Alagesan, Priya, primary, Zaatari, Maya N., primary, Park, Youngkyu, primary, Skepper, Jeremy N., primary, Macleod, Kay F., primary, Perez-Mancera, Pedro A., primary, Murphy, Michael P., primary, Evan, Gerard I., primary, Vousden, Karen H., primary, and Tuveson, David A., primary

Published
2023
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45. Supplementary Data from Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer

Author

Wang, Xiuchao, primary, Li, Yunzhan, primary, Li, Zekun, primary, Lin, Shengchen, primary, Wang, Hongwei, primary, Sun, Jianwei, primary, Lan, Chungen, primary, Wu, Liangliang, primary, Sun, Dongxiao, primary, Huang, Chongbiao, primary, Singh, Pankaj K., primary, Hempel, Nadine, primary, Trebak, Mohamed, primary, DeNicola, Gina M., primary, Hao, Jihui, primary, and Yang, Shengyu, primary

Published
2023
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46. Data from Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer

Author

Wang, Xiuchao, primary, Li, Yunzhan, primary, Li, Zekun, primary, Lin, Shengchen, primary, Wang, Hongwei, primary, Sun, Jianwei, primary, Lan, Chungen, primary, Wu, Liangliang, primary, Sun, Dongxiao, primary, Huang, Chongbiao, primary, Singh, Pankaj K., primary, Hempel, Nadine, primary, Trebak, Mohamed, primary, DeNicola, Gina M., primary, Hao, Jihui, primary, and Yang, Shengyu, primary

Published
2023
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47. Supplementary Table from Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer

Author

Wang, Xiuchao, primary, Li, Yunzhan, primary, Li, Zekun, primary, Lin, Shengchen, primary, Wang, Hongwei, primary, Sun, Jianwei, primary, Lan, Chungen, primary, Wu, Liangliang, primary, Sun, Dongxiao, primary, Huang, Chongbiao, primary, Singh, Pankaj K., primary, Hempel, Nadine, primary, Trebak, Mohamed, primary, DeNicola, Gina M., primary, Hao, Jihui, primary, and Yang, Shengyu, primary

Published
2023
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49. Glutathione supports lipid abundancein vivo

Author

Asantewaa, Gloria, primary, Tuttle, Emily T., additional, Ward, Nathan P., additional, Kang, Yun Pyo, additional, Kim, Yumi, additional, Kavanagh, Madeline E., additional, Girnius, Nomeda, additional, Chen, Ying, additional, Duncan, Renae, additional, Rodriguez, Katherine, additional, Hecht, Fabio, additional, Zocchi, Marco, additional, Smorodintsev-Schiller, Leonid, additional, Scales, TashJaé Q., additional, Taylor, Kira, additional, Alimohammadi, Fatemeh, additional, Sechrist, Zachary R, additional, Agostini-Vulaj, Diana, additional, Schafer, Xenia L., additional, Chang, Hayley, additional, Smith, Zachary, additional, O’Connor, Thomas N., additional, Whelan, Sarah, additional, Selfors, Laura M., additional, Crowdis, Jett, additional, Gray, G. Kenneth, additional, Bronson, Roderick T., additional, Brenner, Dirk, additional, Rufini, Alessandro, additional, Dirksen, Robert T., additional, Hezel, Aram F., additional, Huber, Aaron R., additional, Munger, Josh, additional, Cravatt, Benjamin F., additional, Vasiliou, Vasilis, additional, Cole, Calvin L, additional, DeNicola, Gina M., additional, and Harris, Isaac S., additional

Published
2023
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