12 results on '"DeNicola, Gina"'
Search Results
2. Abstract PO-028: Investigating the contribution of CHAC1 to persistent mitochondrial respiratory function in NSCLC under cysteine deprivation
- Author
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Ward, Nathan P., primary and DeNicola, Gina M., additional
- Published
- 2020
- Full Text
- View/download PDF
3. Abstract C46: Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms
- Author
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Reverón, Dayana, primary, Beato, Francisca, additional, DeNicola, Gina, additional, Ortiz, Antonio, additional, Centeno, Barbara, additional, Jiang, Kun, additional, Jeong, Daniel, additional, Malafa, Mokenge, additional, Hodul, Pamela, additional, Deszi, Kaleena, additional, Permuth, Jennifer, additional, and Fleming, Jason, additional
- Published
- 2019
- Full Text
- View/download PDF
4. Correction: Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
- Author
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Yoon SJ, Combs JA, Falzone A, Prieto-Farigua N, Caldwell S, Ackerman HD, Flores ER, and DeNicola GM
- Published
- 2024
- Full Text
- View/download PDF
5. Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.
- Author
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DeBlasi JM, Falzone A, Caldwell S, Prieto-Farigua N, Prigge JR, Schmidt EE, Chio IIC, Karreth FA, and DeNicola GM
- Subjects
- Animals, Humans, Mice, Carcinogenesis genetics, Cell Line, Tumor, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, Lung pathology, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Signal Transduction
- Abstract
Mutations in the KEAP1-NRF2 (Kelch-like ECH-associated protein 1-nuclear factor-erythroid 2 p45-related factor 2) pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors, p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process., Significance: Stabilization of the transcription factor NRF2 promotes oncogene-driven tumor initiation but blocks tumor progression, indicating distinct, threshold-dependent effects of the KEAP1/NRF2 pathway in different stages of lung tumorigenesis., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
6. Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
- Author
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Yoon SJ, Combs JA, Falzone A, Prieto-Farigua N, Caldwell S, Ackerman HD, Flores ER, and DeNicola GM
- Subjects
- Mice, Animals, Cystine metabolism, Glutathione metabolism, Carcinogenesis, Serine, Mammals metabolism, Cysteine metabolism, Neoplasms
- Abstract
Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and cancers that arise from them using stable isotope 13C1-serine and 13C6-cystine tracing. De novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while cysteine synthesis was either inactive or downregulated during tumorigenesis. In contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. However, differences in glutathione labeling from cysteine were evident across tumor types. Thus, cystine is a major contributor to the cysteine pool in tumors, and glutathione metabolism is differentially active across tumor types., Significance: Stable isotope 13C1-serine and 13C6-cystine tracing characterizes cysteine metabolism in normal murine tissues and its rewiring in tumors using genetically engineered mouse models of liver, pancreas, and lung cancers., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
7. Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.
- Author
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Ravichandran M, Hu J, Cai C, Ward NP, Venida A, Foakes C, Kuljanin M, Yang A, Hennessey CJ, Yang Y, Desousa BR, Rademaker G, Staes AAL, Cakir Z, Jain IH, Aguirre AJ, Mancias JD, Shen Y, DeNicola GM, and Perera RM
- Subjects
- Humans, Biological Availability, Iron metabolism, Iron therapeutic use, Nuclear Receptor Coactivators metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Sulfur metabolism, Sulfur therapeutic use, Transcription Factors metabolism, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Iron-Sulfur Proteins metabolism, Iron-Sulfur Proteins therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism
- 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., Significance: Reduced 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., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
8. Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer.
- Author
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Wang X, Li Y, Li Z, Lin S, Wang H, Sun J, Lan C, Wu L, Sun D, Huang C, Singh PK, Hempel N, Trebak M, DeNicola GM, Hao J, and Yang S
- Subjects
- Calcium metabolism, Cell Line, Tumor, Cystine metabolism, Humans, Kelch-Like ECH-Associated Protein 1 metabolism, NF-E2-Related Factor 2 metabolism, Calcium Channels metabolism, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacologic inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared with MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and to drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and to prevent metastasis., Significance: Elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted to improve pancreatic cancer treatment., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
9. IL1RAP Pulls a Double Shift in the Cysteine Factory.
- Author
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Yoon SJ and DeNicola GM
- Subjects
- Antiporters, Glutamic Acid, Reactive Oxygen Species metabolism, Cysteine, Cystine metabolism
- Abstract
Anoikis is a critical barrier to cancer cell metastasis. In this issue of Cancer Discovery , Zhang and colleagues identify that IL1 receptor accessory protein suppresses anoikis in Ewing sarcoma by promoting both the activity of the system X
c - cystine/glutamate antiporter and cystathionine γ-lyase (CTH) transcription to sustain cysteine levels for reactive oxygen species detoxification. See related article by Zhang et al., p. 2884 ., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF
10. The Golgi: Keeping It Unapologetically Basic.
- Author
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Ward NP and DeNicola GM
- Subjects
- Homeostasis, Humans, Hydrogen-Ion Concentration, Pancreas, Carcinoma, Pancreatic Ductal genetics, Pancreatic Neoplasms drug therapy
- Abstract
Tumor cells maintain a reverse pH gradient relative to normal cells, conferring cell-intrinsic and cell-extrinsic benefits that sustain tumor growth. In this issue of Cancer Discovery , Galenkamp and colleagues reveal that NHE7 mediates acidification of the trans -Golgi network in pancreatic ductal adenocarcinoma, which is critical for the maintenance of cytosolic pH and consequently tumor growth. See related article by Galenkamp et al., p. 822 ., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
11. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.
- Author
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Humpton TJ, Alagesan B, DeNicola GM, Lu D, Yordanov GN, Leonhardt CS, Yao MA, Alagesan P, Zaatari MN, Park Y, Skepper JN, Macleod KF, Perez-Mancera PA, Murphy MP, Evan GI, Vousden KH, and Tuveson DA
- Subjects
- Animals, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glycolysis, Humans, Membrane Proteins genetics, Mice, Mitophagy, Mutation, NADP metabolism, Neoplasm Transplantation, Oxidation-Reduction, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras) metabolism, Tumor Suppressor Proteins genetics, Carcinoma, Pancreatic Ductal pathology, Membrane Proteins metabolism, Mitochondria metabolism, Pancreatic Neoplasms pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins p21(ras) genetics, Tumor Suppressor Proteins metabolism
- Abstract
Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L /NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer. This article is highlighted in the In This Issue feature, p. 1143 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
12. C-Raf is required for the initiation of lung cancer by K-Ras(G12D).
- Author
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Karreth FA, Frese KK, DeNicola GM, Baccarini M, and Tuveson DA
- Subjects
- Animals, Cell Growth Processes physiology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Epithelial Cells metabolism, Epithelial Cells pathology, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Fibroblasts metabolism, Fibroblasts pathology, Lung metabolism, Lung pathology, Lung Neoplasms metabolism, Lung Neoplasms pathology, MAP Kinase Signaling System, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells pathology, Mice, Mice, 129 Strain, Mitogen-Activated Protein Kinases genetics, Mitogen-Activated Protein Kinases metabolism, Mutation genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Transformation, Genetic genetics, Lung Neoplasms enzymology, Lung Neoplasms genetics, Proto-Oncogene Proteins c-raf genetics, Proto-Oncogene Proteins c-raf metabolism, ras Proteins genetics, ras Proteins metabolism
- Abstract
The Ras/Raf/MEK/ERK (extracellular signal-regulated kinase) pathway is primarily responsible for mitogenesis in metazoans, and mutational activation of this pathway is common in cancer. A variety of selective chemical inhibitors directed against the mitogen-activated protein kinase pathway are now available for clinical investigation and thus the determination of the importance of each of the kinases in oncogenesis is paramount. We investigated the role of two Raf kinases, B-Raf and C-Raf, in Ras oncogenesis, and found that although B-Raf and C-Raf have overlapping functions in primary mesenchymal cells, C-Raf but not B-Raf is required for the proliferative effects of K-Ras(G12D) in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-Ras(G12D), whereas B-Raf is dispensable for this process. Our findings reveal that K-Ras(G12D) elicits its oncogenic effects primarily through C-Raf and suggest that selective C-Raf inhibition could be explored as a therapeutic strategy for K-Ras-dependent cancers.
- Published
- 2011
- Full Text
- View/download PDF
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