Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism

Bott, Alex J.; Shen, Jianliang; Tonelli, C.; Zhan, Lin; Sivaram, Nithya; Jiang, Ya; Yu, Xufen; Bhatt, Vrushank; Chiles, Eric; Zhong, Hua; Maimouni, Sara; Dai, Weiwei; Velasquez, Stephani; Pan, Jinyan; Muthalagu, Nathiya; Morton, Jennifer P.; Anthony, Tracy G.; Feng, Hui; Lamers, Wouter H.; Murphy, Daniel J.; Guo, Jessie Yanxiang; Jin, Jian; Crawford, Howard C.; Zhang, Lanjing; White, Eileen; Lin, Richard Z.; Su, Xiaoyang; Tuveson, David A.; Zong, Wei Xing

doi:10.1016/j.celrep.2019.09.056

Cited by 129 publications

(118 citation statements)

References 48 publications

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“…The deprivation of PDA tumor cells of nutrients may also change over time, as tumor growth reshapes 3D cellular organization and the proximity of cancer cells to stroma and endothelial cells. It is therefore not surprising that, unlike Bott et al (34), we found no significant association between average GS levels and tumor grade or patient survival (Fig. S13).…”

Section: Discussioncontrasting

confidence: 69%

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Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Tsai

Lee

Jadhav

et al. 2020

Preprint

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30Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly 31 desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving 32 PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism 33 of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for 34 clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find 35 that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. 36Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino 37 acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity 38 that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for 39 glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open 40 chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and 41 mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA 42 and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients. 43 44 3 stroma restrict nutrient access, remains unknown. 53Because nutrient availability largely dictates metabolic behavior 10 , the relevance of studying 54 tumor metabolism within the native environment has been recently underscored [11][12][13][14][15] . Although culture 55 media composition can be modulated to mimic circulating metabolite levels 16, 17 , this modulation may 56 not accurately reflect the tumor metabolic microenvironment. In particular, levels of glucose and 57 glutamine, two of the most abundant and tumor-preferred nutrients in the circulation, can be limiting in 58 PDA tumors, compared to benign adjacent tissue 7 , and significantly lower within tumor cores, compared 59 to the periphery 18, 19 . Paradoxically, both glucose and glutamine are routinely supplemented in culture 60 media at levels that are significantly higher than the circulation: 11mM glucose and 2mM glutamine in 61 RPMI compared to ~ 5.5mM glucose and 0.6mM glutamine in serum 20 . Although prior studies focused 62 on depriving tumor cells of either glucose or glutamine alone 9, 21-24 , how PDA cells survive and 63 proliferate under limiting levels of both major nutrients is not well understood. 64To investigate this, we selected for clonal PDA cells that survive and adapt to limiting levels of 65 both glucose and glutamine. We find that the adapted clones have enhanced proliferation in vitro and 66 tumor-forming capacity in vivo. They also share common signaling, transcriptional and metabolic 67 alterations that are acquired upon adaptation. These include a post-translational role for mTORC1 68 signaling in the stabilization of glutamine synthetase (GS), and the use of amino acids for the synthesis...

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Section: Discussioncontrasting

confidence: 69%

“…Nevertheless, based on our results and those of Bott et al (34), targeting GS in the nutrient-deprived PDA tumors holds significant therapeutic value in pancreatic cancer.…”

Section: Pda Cells Adapted To Nutrient-deprived Conditions Are Sensitsupporting

confidence: 70%

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Tsai

Lee

Jadhav

et al. 2020

Preprint

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“…In addition to KRAS, other genetic alterations related to amino acid metabolism enzymes have been implicated in the pathogenesis of PDAC. Genetic ablation of Bcat2 , endothelial NOS ( eNOS ), and glutamate ammonia ligase ( GLUL ) could attenuate PanIN progression ( 23 , 83 , 84 ). Moreover, genetic alterations have also been demonstrated to drive tumorigenesis through coupled metabolic and epigenetic reprogramming.…”

Section: Amino Acid Metabolism Regulates Pdac Development and Progresmentioning

confidence: 99%

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

Yang

Ren

et al. 2020

Front. Oncol.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.

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“…Targeting cancer metabolism is a promising therapeutic strategy, and metabolic reprogramming driven by oncogenes enables PDACs to survive in hypoxic and nutrient-deprived microenvironments [ 11 ]. For example, oncogenic KRAS, present in more than 95% of PDAC tumors, upregulates glutamine metabolism for supporting its biosynthetic needs and maintaining redox homeostasis [ 12 , 13 ]. Glutamine is indispensable for PDAC growth as it serves as a carbon donor for TCA cycle anaplerosis and nitrogen donor for nucleotide biosynthesis and amino acid generation [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells

Srivastava

Widmann

et al. 2020

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.

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Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism

Cited by 129 publications

References 48 publications

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells

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