bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023‒06‒04
fifteen papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition.
  2. Targeting Glutamine Metabolism as an Attractive Therapeutic Strategy for Acute Myeloid Leukemia.
  3. Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis.
  4. PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response.
  5. Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
  6. Integrating multiple machine learning methods to construct glutamine metabolism-related signatures in lung adenocarcinoma.
  7. pH-Sensitive Tumor-Tropism Hybrid Membrane-Coated Nanoparticles for Reprogramming the Tumor Microenvironment and Boosting the Antitumor Immunity.
  8. Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
  9. Nutrient sensors and their crosstalk.
  10. Metabolism in the tumour cell and beyond.
  11. Quantification and Tracing of Stable Isotope into Cysteine and Glutathione.
  12. Is metabolism the magic bullet for targeted cancer therapy?
  13. Bulk and single-cell transcriptome profiling reveal the metabolic heterogeneity in gastric cancer.
  14. Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via Nur77-mediated epigenetic regulation of GLS1.
  15. Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy.
  1. Front Nutr. 2023 ;10 1124678
    A metabolic shift toward glycolysis enables cancer cells to maintain survival upon concomitant glutamine deprivation and V-ATPase inhibition.
    Florian Lengauer, Franz Geisslinger, Antje Gabriel, Karin von Schwarzenberg, Angelika M Vollmar, Karin Bartel.
      It is widely known that most cancer cells display an increased reliance on glutaminolysis to sustain proliferation and survival. Combining glutamine deprivation with additional anti-cancer therapies is an intensively investigated approach to increase therapeutic effectiveness. In this study, we examined a combination of glutamine deprivation by starvation or pharmacological tools, with the anti-cancer agent archazolid, an inhibitor of the lysosomal V-ATPase. We show that glutamine deprivation leads to lysosomal acidification and induction of pro-survival autophagy, which could be prevented by archazolid. Surprisingly, a combination of glutamine deprivation with archazolid did not lead to synergistic induction of cell death or reduction in proliferation. Investigating the underlying mechanisms revealed elevated expression and activity of amino acid transporters SLC1A5, SLC38A1 upon starvation, whereas archazolid had no additional effect. Furthermore, we found that the export of lysosomal glutamine derived from exogenous sources plays no role in the phenotype as knock-down of SLC38A7, the lysosomal glutamine exporter, could not increase V-ATPase inhibition-induced cell death or reduce proliferation. Analysis of the cellular metabolic phenotype revealed that glutamine deprivation led to a significant increase in glycolytic activity, indicated by an elevated glycolytic capacity and reserve, when V-ATPase function was inhibited concomitantly. This was confirmed by increased glutamine uptake, augmented lactate production, and an increase in hexokinase activity. Our study, therefore, provides evidence, that glutamine deprivation induces autophagy, which can be prevented by simultaneous inhibition of V-ATPase function. However, this does not lead to a therapeutic benefit, as cells are able to circumvent cell death and growth inhibition by a metabolic shift toward glycolysis.
    Keywords:  V-ATPase; cancer; cancer metabolism; glutamine; glycolysis
    DOI:  https://doi.org/10.3389/fnut.2023.1124678
  2. Curr Treat Options Oncol. 2023 May 30.
    Targeting Glutamine Metabolism as an Attractive Therapeutic Strategy for Acute Myeloid Leukemia.
    Yan Xiao, Bingbing Hu, Yao Guo, Dengyang Zhang, Yuming Zhao, Yun Chen, Na Li, Liuting Yu.
      OPINION STATEMENT: Relapse after chemotherapy and hematopoietic stem cell transplantation leads to adverse prognosis for acute myeloid leukemia (AML) patients. As a "conditionally essential amino acid," glutamine contributes to the growth and proliferation of AML cells. Glutamine-target strategies as new treatment approaches have been widely explored in AML treatment to improve outcome. Glutamine-target strategies including depletion of systemic glutamine and application of glutamine uptake inhibitors, glutamine antagonists/analogues, and glutaminase inhibitors. Because glutamine metabolism involved in multiple pathways in cells and each pathway of glutamine metabolism has many regulatory factors, therefore, AML therapy targeting glutamine metabolism should focus on how to inhibit multiple metabolic pathways without affecting normal cells and host immune to achieve effective treatment for AML.
    Keywords:  AML treatment; Acute myeloid leukemia; Cancer metabolism; Glutaminase inhibitor; Glutamine; Glutamine antagonist
    DOI:  https://doi.org/10.1007/s11864-023-01104-0
  3. Proc Natl Acad Sci U S A. 2023 Jun 06. 120(23): e2217869120
    Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis.
    Wei Li, Junjie Kou, Zhenxi Zhang, Haoyue Li, Li Li, Wenjing Du.
      T cell lymphomas (TCLs) are a group of rare and heterogeneous tumors. Although proto-oncogene MYC has an important role in driving T cell lymphomagenesis, whether MYC carries out this function remains poorly understood. Here, we show that malic enzyme 2 (ME2), one of the NADPH-producing enzymes associated with glutamine metabolism, is essential for MYC-driven T cell lymphomagenesis. We establish a CD4-Cre; Myc flox/+transgenic mouse mode, and approximately 90% of these mice develop TCL. Interestingly, knockout of Me2 in Myc transgenic mice almost completely suppresses T cell lymphomagenesis. Mechanistically, by transcriptionally up-regulating ME2, MYC maintains redox homeostasis, thereby increasing its tumorigenicity. Reciprocally, ME2 promotes MYC translation by stimulating mTORC1 activity through adjusting glutamine metabolism. Treatment with rapamycin, an inhibitor of mTORC1, blocks the development of TCL both in vitro and in vivo. Therefore, our findings identify an important role for ME2 in MYC-driven T cell lymphomagenesis and reveal that MYC-ME2 circuit may be an effective target for TCL therapy.
    Keywords:  MYC; T cell lymphomas; glutamine metabolism; malic enzyme 2; redox homeostasis
    DOI:  https://doi.org/10.1073/pnas.2217869120
  4. Front Oncol. 2023 ;13 1125855
    PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response.
    Barbara Zerbato, Maximilian Gobbi, Tobias Ludwig, Virginia Brancato, Alex Pessina, Luca Brambilla, Andre Wegner, Ferdinando Chiaradonna.
      Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor patient prognosis. Remarkably, PDAC is one of the most aggressive and deadly tumor types and is notorious for its resistance to all types of treatment. PDAC resistance is frequently associated with a wide metabolic rewiring and in particular of the glycolytic branch named Hexosamine Biosynthetic Pathway (HBP).Methods: Transcriptional and bioinformatics analysis were performed to obtain information about the effect of the HBP inhibition in two cell models of PDAC. Cell count, western blot, HPLC and metabolomics analyses were used to determine the impact of the combined treatment between an HBP's Phosphoglucomutase 3 (PGM3) enzyme inhibitor, named FR054, and erastin (ERA), a recognized ferroptosis inducer, on PDAC cell growth and survival.
    Results: Here we show that the combined treatment applied to different PDAC cell lines induces a significant decrease in cell proliferation and a concurrent enhancement of cell death. Furthermore, we show that this combined treatment induces Unfolded Protein Response (UPR), NFE2 Like BZIP Transcription Factor 2 (NRF2) activation, a change in cellular redox state, a greater sensitivity to oxidative stress, a major dependence on glutamine metabolism, and finally ferroptosis cell death.
    Conclusion: Our study discloses that HBP inhibition enhances, via UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy.
    Keywords:  cell death; erastin; ferroptosis; hexosamine biosynthetic pathway; pancreatic cancer cells; unfolded protein response
    DOI:  https://doi.org/10.3389/fonc.2023.1125855
  5. Elife. 2023 May 31. pii: e81289. [Epub ahead of print]12
    Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
    Juan J Apiz Saab, Lindsey N Dzierozynski, Patrick B Jonker, Roya AminiTabrizi, Hardik Shah, Rosa Elena Menjivar, Andrew J Scott, Zeribe C Nwosu, Zhou Zhu, Riona N Chen, Moses Oh, Colin Sheehan, Daniel R Wahl, Marina Pasca di Magliano, Costas A Lyssiotis, Kay F Macleod, Christopher R Weber, Alexander Muir.
      Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors (M. R. Sullivan, Danai, et al., 2019). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.81289
  6. Front Endocrinol (Lausanne). 2023 ;14 1196372
    Integrating multiple machine learning methods to construct glutamine metabolism-related signatures in lung adenocarcinoma.
    Pengpeng Zhang, Shengbin Pei, Leilei Wu, Zhijia Xia, Qi Wang, Xufeng Huang, Zhangzuo Li, Jiaheng Xie, Mingjun Du, Haoran Lin.
      Background: Glutamine metabolism (GM) is known to play a critical role in cancer development, including in lung adenocarcinoma (LUAD), although the exact contribution of GM to LUAD remains incompletely understood. In this study, we aimed to discover new targets for the treatment of LUAD patients by using machine learning algorithms to establish prognostic models based on GM-related genes (GMRGs).Methods: We used the AUCell and WGCNA algorithms, along with single-cell and bulk RNA-seq data, to identify the most prominent GMRGs associated with LUAD. Multiple machine learning algorithms were employed to develop risk models with optimal predictive performance. We validated our models using multiple external datasets and investigated disparities in the tumor microenvironment (TME), mutation landscape, enriched pathways, and response to immunotherapy across various risk groups. Additionally, we conducted in vitro and in vivo experiments to confirm the role of LGALS3 in LUAD.
    Results: We identified 173 GMRGs strongly associated with GM activity and selected the Random Survival Forest (RSF) and Supervised Principal Components (SuperPC) methods to develop a prognostic model. Our model's performance was validated using multiple external datasets. Our analysis revealed that the low-risk group had higher immune cell infiltration and increased expression of immune checkpoints, indicating that this group may be more receptive to immunotherapy. Moreover, our experimental results confirmed that LGALS3 promoted the proliferation, invasion, and migration of LUAD cells.
    Conclusion: Our study established a prognostic model based on GMRGs that can predict the effectiveness of immunotherapy and provide novel approaches for the treatment of LUAD. Our findings also suggest that LGALS3 may be a potential therapeutic target for LUAD.
    Keywords:  glutamine; lung adenocarcinoma; machine learning; prognosis; signature
    DOI:  https://doi.org/10.3389/fendo.2023.1196372
  7. Acta Biomater. 2023 May 28. pii: S1742-7061(23)00303-3. [Epub ahead of print]
    pH-Sensitive Tumor-Tropism Hybrid Membrane-Coated Nanoparticles for Reprogramming the Tumor Microenvironment and Boosting the Antitumor Immunity.
    Jie Zhang, Liwen Wei, Xiaocao Ma, Jingguo Wang, Siping Liang, Kang Chen, Minhao Wu, Li Niu, Yuanqing Zhang.
      Metabolic dysregulation contributes not only to cancer development but also to a tumor immune microenvironment (TIME), which poses great challenges to chemo- and immunotherapy. Targeting metabolic reprogramming has recently emerged as a promising strategy for cancer treatment, but the lethality against solid tumors appears to be fairly restricted, partially due to the poor solubility of small molecule drugs. Herein, we construct a versatile biomimetic nanoplatform (referred to as HM-BPT) employing pH-sensitive tumor-tropism hybrid membrane-coated Manganese oxide (MnO2) nanoparticles for the delivery of BPTES, a glutamine metabolism inhibitor. Basically, hybrid membranes consisting of mesenchymal stem cell membranes (MSCm) and pH-sensitive liposomes (pSL) enable the biomimetic nanoplatform to target TME and escape from endo/lysosomes after endocytosis. The results reveal that HM-BPT treatment leads to remarkable tumor inhibition, cytotoxic T lymphocyte (CTL) infiltration, as well as M1 phenotype repolarization and stimulator of IFN genes (STING) pathway activation in macrophages in a 4T1 xenograft model. Furthermore, glutathione (GSH) depletion and oxygen (O2) supply synergistically ameliorate the immunosuppressive status of the TME, boosting potent antitumor immune responses. Overall, our study explores an integrated therapeutic platform for TME reprogramming and immune activation, offering tremendous promise for cancer combination therapy. STATEMENT OF SIGNIFICANCE: Metabolic abnormalities and the tumor immune microenvironment (TIME) lead to hyporesponsiveness to conventional therapies, ultimately resulting in refractory malignancies. In the current work, a biomimetic nanoplatform (HM-BPT) was developed for TME metabolic reprogramming in favor of immunotherapy. Particularly, hybrid membrane camouflage endowed the nanoplatform with TME targeting, endo/lysosomal escape, and sensitive release properties. The impact of hybrid membrane fusion ratio on cellular uptake and cell viability was explored, yielding beneficial references for the future development of bioactive nanomaterials. Intravenous administration of HM-BPT substantially relieved tumor burden and restored innate and acquired immune activation in 4T1 xenograft models. In conclusion, the created HM-BPT system has the potential to be a promising nanoplatform for combining cancer therapies.
    Keywords:  STING; cancer combination therapy; metabolic reprogramming; pH-sensitive; tumor tropism
    DOI:  https://doi.org/10.1016/j.actbio.2023.05.040
  8. Nat Cancer. 2023 May 29.
    Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
    Pravat Kumar Parida, Mauricio Marquez-Palencia, Suvranil Ghosh, Nitin Khandelwal, Kangsan Kim, Vidhya Nair, Xiao-Zheng Liu, Hieu S Vu, Lauren G Zacharias, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bret C Mobley, Jeffrey G McDonald, Andrew Lemoff, Yan Peng, Cheryl Lewis, Gonçalo Vale, Nils Halberg, Carlos L Arteaga, Ariella B Hanker, Ralph J DeBerardinis, Srinivas Malladi.
      Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.
    DOI:  https://doi.org/10.1038/s43018-023-00563-6
  9. Exp Mol Med. 2023 Jun 01.
    Nutrient sensors and their crosstalk.
    Yulseung Sung, Ya Chun Yu, Jung Min Han.
      The macronutrients glucose, lipids, and amino acids are the major components that maintain life. The ability of cells to sense and respond to fluctuations in these nutrients is a crucial feature for survival. Nutrient-sensing pathways are thus developed to govern cellular energy and metabolic homeostasis and regulate diverse biological processes. Accordingly, perturbations in these sensing pathways are associated with a wide variety of pathologies, especially metabolic diseases. Molecular sensors are the core within these sensing pathways and have a certain degree of specificity and affinity to sense the intracellular fluctuation of each nutrient either by directly binding to that nutrient or indirectly binding to its surrogate molecules. Once the changes in nutrient levels are detected, sensors trigger signaling cascades to fine-tune cellular processes for energy and metabolic homeostasis, for example, by controlling uptake, de novo synthesis or catabolism of that nutrient. In this review, we summarize the major discoveries on nutrient-sensing pathways and explain how those sensors associated with each pathway respond to intracellular nutrient availability and how these mechanisms control metabolic processes. Later, we further discuss the crosstalk between these sensing pathways for each nutrient, which are intertwined to regulate overall intracellular nutrient/metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s12276-023-01006-z
  10. Mol Oncol. 2023 May 27.
    Metabolism in the tumour cell and beyond.
    Arkaitz Carracedo.
      The process of cellular transformation encompasses the acquisition of key and distinctive features, commonly known as hallmarks of cancer. These hallmarks are supported by tumour-intrinsic molecular alterations as well as changes in the microenvironment. Cellular metabolism represents one of the most intimate connections between a cell and the environment. In turn, metabolic adaptation represents a research field of increasing interest in cancer biology. In this viewpoint, I will provide a panoramic perspective of the relevance and repercussions of metabolic alterations in tumours with non-exhaustive illustrative examples and speculate the prospects of cancer metabolism research.
    Keywords:  Cancer metabolism; anabolism; metabolic vulnerability; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.13467
  11. Methods Mol Biol. 2023 ;2675 51-63
    Quantification and Tracing of Stable Isotope into Cysteine and Glutathione.
    Yun Pyo Kang, Gina M DeNicola.
      The analysis of metabolic perturbation in biological samples is crucial to understand mechanisms of metabolic diseases. Here, we describe a protocol for quantitative stable isotope-labeled metabolite tracing of cysteine metabolism in cultured cells. This protocol relies on an extraction protocol to derivatize free thiols to prevent oxidation. In addition, the quantitative tracing of serine into multiple pathways, including the glutathione synthesis pathway, allows for the interrogation of cysteine and glutathione synthesis. This protocol provides a flexible framework that can be adapted to interrogate many metabolites and pathways of interest.
    Keywords:  Cell culture; Cysteine; Mass spectrometry; Quantification; Serine; Stable isotope standard; Stable isotope tracing
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_5
  12. BMC Cancer. 2023 May 30. 23(1): 484
    Is metabolism the magic bullet for targeted cancer therapy?
    Marija Trajkovic-Arsic, Elavarasan Subramani.
      Altered cellular metabolism has long been recognized as a hallmark of cancer. Oncogenic signaling cascades induce metabolic rewiring that further supports tumorigenesis, therapy resistance and metastasis. In view of this, the Collection on 'Cancer Metabolism' highlights the current views and focus of research on personalized medicine approach to target metabolism for cancer therapy.
    DOI:  https://doi.org/10.1186/s12885-023-10999-9
  13. Sci Rep. 2023 May 31. 13(1): 8787
    Bulk and single-cell transcriptome profiling reveal the metabolic heterogeneity in gastric cancer.
    Guoqiang Tao, Xiangyu Wen, Xingxing Wang, Qi Zhou.
      Metabolic reprogramming has been defined as a key hall mark of human tumors. However, metabolic heterogeneity in gastric cancer has not been elucidated. Here we separated the TCGA-STAD dataset into two metabolic subtypes. The differences between subtypes were elaborated in terms of transcriptomics, genomics, tumor-infiltrating cells, and single-cell resolution. We found that metabolic subtype 1 is predominantly characterized by low metabolism, high immune cell infiltration. Subtype 2 is mainly characterized by high metabolism and low immune cell infiltration. From single-cell resolution, we found that the high metabolism of subtype 2 is dominated by epithelial cells. Not only epithelial cells, but also various immune cells and stromal cells showed high metabolism in subtype 2 and low metabolism in subtype 1. Our study established a classification of gastric cancer metabolic subtypes and explored the differences between subtypes from multiple dimensions, especially the single-cell resolution.
    DOI:  https://doi.org/10.1038/s41598-023-35395-y
  14. Br J Pharmacol. 2023 Jun 01.
    Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via Nur77-mediated epigenetic regulation of GLS1.
    Li Chen, Baoyu Liang, Siwei Xia, Feixia Wang, Zhanghao Li, Jiangjuan Shao, Zili Zhang, Anping Chen, Shizhong Zheng, Feng Zhang.
      BACKGROUND AND PURPOSE: Senescence in hepatic stellate cells (HSCs) limits liver fibrosis. Glutaminolysis promotes HSC activation. We here investigated how emodin affected HSC senescence involving glutaminolysis.EXPERIMENTAL APPROACH: Senescence, glutaminolysis metabolites, Nur77 nuclear translocation, glutaminase 1 (GLS1) promoter methylation, and related signaling pathways were examined in human HSC-LX2 cells using multiple cellular and molecular approaches. Fibrotic mice with shRNA-mediated knockdown of Nur77 were treated with emodin-vitamin A liposome for investigating the mechanisms in vivo. Human fibrotic liver samples were examined to verify the clinical relevance.
    KEY RESULTS: Emodin upregulated several key markers of senescence and inhibited glutaminolysis cascade in HSCs. Emodin promoted Nur77 nuclear translocation, and knockdown of Nur77 abolished emodin blockade of glutaminolysis and induction of HSC senescence. Mechanically, emodin facilitated Nur77/DNMT3b interaction and increased GLS1 promoter methylation, leading to inhibited GLS1 expression and blockade of glutaminolysis. Moreover, glutaminolysis intermediate α-ketoglutarate promoted extracellular signal-regulated kinase (ERK) phosphorylation, which in turn phosphorylated Nur77 and reduced its interaction with DNMT3b. This led to decreased GLS1 promoter methylation and increased GLS1 expression, forming an ERK/Nur77/glutaminolysis positive feedback loop. However, emodin repressed ERK phosphorylation and interrupted the feedback cascade, stimulating senescence in HSCs. Studies in mice showed that emodin-vitamin A liposome inhibited glutaminolysis and induced senescence in HSCs, and consequently alleviated liver fibrosis; but knockdown of Nur77 abrogated these beneficial effects. Similar alterations were validated in human fibrotic liver tissues.
    CONCLUSIONS AND IMPLICATIONS: Emodin stimulated HSC senescence through interruption of glutaminolysis. HSC-targeted delivery of emodin represented a therapeutic option for liver fibrosis.
    Keywords:  Nur77; emodin; glutaminolysis; hepatic stellate cell; liver fibrosis; methylation; senescence
    DOI:  https://doi.org/10.1111/bph.16156
  15. Chin Med J (Engl). 2023 May 29.
    Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy.
    Mingyang Shao, Qing Tao, Yahong Xu, Qing Xu, Yuke Shu, Yuwei Chen, Junyi Shen, Yongjie Zhou, Zhenru Wu, Menglin Chen, Jiayin Yang, Yujun Shi, Tianfu Wen, Hong Bu.
      BACKGROUND: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear.METHODS: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted.
    RESULTS: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways.
    CONCLUSIONS: GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.
    DOI:  https://doi.org/10.1097/CM9.0000000000002380
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