Suppression of Pyruvate carboxylase in E0771 tumors [in vivo]
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ABSTRACT:
PROVIDER: PRJNA821608 | ENA |
REPOSITORIES: ENA
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Project description:suppression of Pyruvate carboxylase in E0771 cells [in vitro]
| PRJNA821607 | ENA
Project description:Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
2023-12-29 | GSE199829 | GEO
Project description:suppression of Pyruvate carboxylase
| PRJNA821599 | ENA
Project description:suppression of Pyruvate carboxylase in M-wnt tumors
| PRJNA821609 | ENA
Project description:Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
2023-12-29 | GSE199830 | GEO
Project description:Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.
2023-12-29 | GSE199828 | GEO
Project description:Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here we have generated mice with a liver specific knockout of Pcx to understand its role in hepatic mitochondrial metabolism under disparate physiological states including a 24 hour fast, as well as ketogenic and high fat diets. These data ultimately show the requirement of Pcx-mediated anapleorsis in the liver under disparate metabolic conditions.
2022-10-31 | GSE198317 | GEO
Project description:Transcriptional profile of wild type L. monocytogenes (EGDe) and a pycA mutant strain was compared on growth in BHI. The human pathogen L. monocytogenes is a facultatively intracellular bacterium that survives and replicates in the cytosol of many mammalian cells. The listerial metabolism, especially under intracellular conditions , is still poorly understood. Recent studies analyzed the carbon metabolism of L. monocytogenes by the 13C-isotopologue perturbation method in a defined minimal medium containing [U-13C6]glucose. It was shown that these bacteria produce oxaloacetate mainly by carboxylation of pyruvate due to an incomplete tricarboxylic acid cycle. Here we report that a pycA insertion mutant defective in pyruvate carboxylase (PYC) still grows, albeit at a reduced rate, in BHI medium, but is unable to multiply in a defined minimal medium with glucose or glycerol 36 as carbon source. Transcriptional profiling was performed on the pycA mutant and the wild type strain grown in BHI to get a closer insight into the effect of the pycA mutation in Listeria monocytogenes. RNA from the two strains were isolated after growth in BHI and and compared using whole genome oligonucleotide microarrays
2010-02-09 | E-GEOD-19014 | biostudies-arrayexpress
Project description:Transcriptional profile of wild type L. monocytogenes (EGDe) and a pycA mutant strain was compared on growth in BHI. The human pathogen L. monocytogenes is a facultatively intracellular bacterium that survives and replicates in the cytosol of many mammalian cells. The listerial metabolism, especially under intracellular conditions , is still poorly understood. Recent studies analyzed the carbon metabolism of L. monocytogenes by the 13C-isotopologue perturbation method in a defined minimal medium containing [U-13C6]glucose. It was shown that these bacteria produce oxaloacetate mainly by carboxylation of pyruvate due to an incomplete tricarboxylic acid cycle. Here we report that a pycA insertion mutant defective in pyruvate carboxylase (PYC) still grows, albeit at a reduced rate, in BHI medium, but is unable to multiply in a defined minimal medium with glucose or glycerol 36 as carbon source. Transcriptional profiling was performed on the pycA mutant and the wild type strain grown in BHI to get a closer insight into the effect of the pycA mutation in Listeria monocytogenes.
2010-02-10 | GSE19014 | GEO
Project description:The aberrant production of collagen by fibroblasts is a hallmark of many solid tumors and can influence cancer progression. How fibroblasts produce collagen within tumor microenvironments which are nutrient-poor is not understood. Here, we show that pyruvate carboxylase (PC) activity increases in fibroblasts cultured in a low glutamine environment, and that PC is required for collagen production by tumor-associated fibroblasts in vivo.
2021-09-03 | GSE169588 | GEO