The Experts below are selected from a list of 10125 Experts worldwide ranked by ideXlab platform
Shruti Bhargava - One of the best experts on this subject based on the ideXlab platform.
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STEM-22. TARGETING Pyrimidine Synthesis ACCENTUATES MOLECULAR THERAPY RESPONSE IN GLIOBLASTOMA STEM CELLS
Neuro-Oncology, 2019Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti BhargavaAbstract:Abstract Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo Pyrimidine Synthesis. Targeting the Pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the Pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through Pyrimidine Synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of Pyrimidine Synthesis and GSC tumorigenic capacity. Higher expression of Pyrimidine Synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
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Targeting Pyrimidine Synthesis accentuates molecular therapy response in glioblastoma stem cells.
Science translational medicine, 2019Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti BhargavaAbstract:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo Pyrimidine Synthesis. Targeting the Pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the Pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through Pyrimidine Synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of Pyrimidine Synthesis and GSC tumorigenic capacity in vitro. Higher expression of Pyrimidine Synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
Daniel Helbling - One of the best experts on this subject based on the ideXlab platform.
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Abstract PR05: Aspartate metabolism links the urea cycle with nucleic acid Synthesis in cancerous proliferation
Cancer Metabolic Pathways, 2016Co-Authors: Shiran Rabinovich, Keren Yizhak, Qin Sun, Alexander Brandis, Daniel Helbling, David Dimmock, Sandesh C Sreenath Nagamani, Eytan Ruppin, Ayelet ErezAbstract:Argininosuccinate synthase (ASS1) is a urea cycle cytosolic enzyme that conjugates aspartate transported across the mitochondria and citrulline. In the liver, this is a critical step in conversion of nitrogenous waste to urea, whereas in most other tissues, it is the penultimate step in arginine Synthesis. Citrullinemia is a urea cycle disorder caused by germline mutations that lead to decreased flux through ASS1. Citrullinemia type I (CTLN I) is caused by ASS1 deficiency and citrullinemia type II (CTLN II) is caused by deficiency in mitochondrial aspartate transporter Citrin. In contrast to the established role of ASS1 in ureagenesis, it was found to be somatically silenced in multiple cancers for which the purpose is unknown. Whereas ASS1 silencing renders the tumors auxotrophic for arginine, we hypothesized that down-regulation of ASS1 has an arginine-independent survival effect by redirecting of aspartate towards Pyrimidine Synthesis. Supported by computational modeling and using multiple methodologies including studies of fibroblasts from patients with CTLN I and CTLN II, cancer cells, clinical data, robust informatics analysis of multiple tumors, we show that ASS1 is a key regulator of the mitochondria-derived aspartate flux. Silencing of ASS1, leads to preferential diversion of aspartate away from the Synthesis of arginine and urea to Pyrimidine Synthesis. Decreasing aspartate flux to Pyrimidine Synthesis by either expressing ASS1 in cancer cells that have endogenous silencing, or by blocking the transport of aspartate through the mitochondrial membrane by inhibiting Citrin, decreases cell proliferation due to decreased nucleic acid Synthesis. Our results demonstrate that ASS1 silencing is a novel mechanism to support nucleic acid Synthesis in cancers and provides the first metabolic link between the urea cycle enzymes and Pyrimidine Synthesis. Citation Format: Shiran Rabinovich, Keren Yizhak, Qin Sun, Alexander Brandis, Daniel Helbling, David Dimmock, Sandesh Nagamani, Eytan Ruppin, Ayelet Erez. Aspartate metabolism links the urea cycle with nucleic acid Synthesis in cancerous proliferation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR05.
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diversion of aspartate in ass1 deficient tumours fosters de novo Pyrimidine Synthesis
Nature, 2015Co-Authors: Shiran Rabinovich, Lital Adler, Keren Yizhak, Alona Sarver, Alon Silberman, Shani Agron, Noa Stettner, Qin Sun, Alexander Brandis, Daniel HelblingAbstract:ASS1, a urea cycle enzyme, promotes cancer cell proliferation by facilitating Pyrimidine Synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation.
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diversion of aspartate in ass1 deficient tumours fosters de novo Pyrimidine Synthesis
Nature, 2015Co-Authors: Shiran Rabinovich, Lital Adler, Keren Yizhak, Alona Sarver, Alon Silberman, Shani Agron, Noa Stettner, Qin Sun, Alexander Brandis, Daniel HelblingAbstract:Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating Pyrimidine Synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased Pyrimidine Synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or Pyrimidine Synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and Pyrimidine Synthesis.
Xiuxing Wang - One of the best experts on this subject based on the ideXlab platform.
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STEM-22. TARGETING Pyrimidine Synthesis ACCENTUATES MOLECULAR THERAPY RESPONSE IN GLIOBLASTOMA STEM CELLS
Neuro-Oncology, 2019Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti BhargavaAbstract:Abstract Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo Pyrimidine Synthesis. Targeting the Pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the Pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through Pyrimidine Synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of Pyrimidine Synthesis and GSC tumorigenic capacity. Higher expression of Pyrimidine Synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
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Targeting Pyrimidine Synthesis accentuates molecular therapy response in glioblastoma stem cells.
Science translational medicine, 2019Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti BhargavaAbstract:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo Pyrimidine Synthesis. Targeting the Pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the Pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through Pyrimidine Synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of Pyrimidine Synthesis and GSC tumorigenic capacity in vitro. Higher expression of Pyrimidine Synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
Kailin Yang - One of the best experts on this subject based on the ideXlab platform.
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STEM-22. TARGETING Pyrimidine Synthesis ACCENTUATES MOLECULAR THERAPY RESPONSE IN GLIOBLASTOMA STEM CELLS
Neuro-Oncology, 2019Co-Authors: Kailin Yang, Xiuxing Wang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti BhargavaAbstract:Abstract Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo Pyrimidine Synthesis. Targeting the Pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the Pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through Pyrimidine Synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of Pyrimidine Synthesis and GSC tumorigenic capacity. Higher expression of Pyrimidine Synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
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Targeting Pyrimidine Synthesis accentuates molecular therapy response in glioblastoma stem cells.
Science translational medicine, 2019Co-Authors: Xiuxing Wang, Kailin Yang, Leo J.y. Kim, Andrew R. Morton, Ryan C. Gimple, Briana C. Prager, Yu Shi, Wenchao Zhou, Shruti BhargavaAbstract:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo Pyrimidine Synthesis. Targeting the Pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the Pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through Pyrimidine Synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of Pyrimidine Synthesis and GSC tumorigenic capacity in vitro. Higher expression of Pyrimidine Synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
Shiran Rabinovich - One of the best experts on this subject based on the ideXlab platform.
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Abstract PR05: Aspartate metabolism links the urea cycle with nucleic acid Synthesis in cancerous proliferation
Cancer Metabolic Pathways, 2016Co-Authors: Shiran Rabinovich, Keren Yizhak, Qin Sun, Alexander Brandis, Daniel Helbling, David Dimmock, Sandesh C Sreenath Nagamani, Eytan Ruppin, Ayelet ErezAbstract:Argininosuccinate synthase (ASS1) is a urea cycle cytosolic enzyme that conjugates aspartate transported across the mitochondria and citrulline. In the liver, this is a critical step in conversion of nitrogenous waste to urea, whereas in most other tissues, it is the penultimate step in arginine Synthesis. Citrullinemia is a urea cycle disorder caused by germline mutations that lead to decreased flux through ASS1. Citrullinemia type I (CTLN I) is caused by ASS1 deficiency and citrullinemia type II (CTLN II) is caused by deficiency in mitochondrial aspartate transporter Citrin. In contrast to the established role of ASS1 in ureagenesis, it was found to be somatically silenced in multiple cancers for which the purpose is unknown. Whereas ASS1 silencing renders the tumors auxotrophic for arginine, we hypothesized that down-regulation of ASS1 has an arginine-independent survival effect by redirecting of aspartate towards Pyrimidine Synthesis. Supported by computational modeling and using multiple methodologies including studies of fibroblasts from patients with CTLN I and CTLN II, cancer cells, clinical data, robust informatics analysis of multiple tumors, we show that ASS1 is a key regulator of the mitochondria-derived aspartate flux. Silencing of ASS1, leads to preferential diversion of aspartate away from the Synthesis of arginine and urea to Pyrimidine Synthesis. Decreasing aspartate flux to Pyrimidine Synthesis by either expressing ASS1 in cancer cells that have endogenous silencing, or by blocking the transport of aspartate through the mitochondrial membrane by inhibiting Citrin, decreases cell proliferation due to decreased nucleic acid Synthesis. Our results demonstrate that ASS1 silencing is a novel mechanism to support nucleic acid Synthesis in cancers and provides the first metabolic link between the urea cycle enzymes and Pyrimidine Synthesis. Citation Format: Shiran Rabinovich, Keren Yizhak, Qin Sun, Alexander Brandis, Daniel Helbling, David Dimmock, Sandesh Nagamani, Eytan Ruppin, Ayelet Erez. Aspartate metabolism links the urea cycle with nucleic acid Synthesis in cancerous proliferation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR05.
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diversion of aspartate in ass1 deficient tumours fosters de novo Pyrimidine Synthesis
Nature, 2015Co-Authors: Shiran Rabinovich, Lital Adler, Keren Yizhak, Alona Sarver, Alon Silberman, Shani Agron, Noa Stettner, Qin Sun, Alexander Brandis, Daniel HelblingAbstract:ASS1, a urea cycle enzyme, promotes cancer cell proliferation by facilitating Pyrimidine Synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation.
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diversion of aspartate in ass1 deficient tumours fosters de novo Pyrimidine Synthesis
Nature, 2015Co-Authors: Shiran Rabinovich, Lital Adler, Keren Yizhak, Alona Sarver, Alon Silberman, Shani Agron, Noa Stettner, Qin Sun, Alexander Brandis, Daniel HelblingAbstract:Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating Pyrimidine Synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased Pyrimidine Synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or Pyrimidine Synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and Pyrimidine Synthesis.
