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Narayanan A, Saurty-Seerunghen MS, Michieletto J, Delaunay V, Bruneel A, Dupré T, Ottolenghi C, Pontoizeau C, Ciccone L, De La Vara A, Idbaih A, Turchi L, Virolle T, Chneiweiss H, Junier MP, El-Habr EA. Nicotinamide metabolism reprogramming drives reversible senescence of glioblastoma cells. Cell Mol Life Sci 2025; 82:126. [PMID: 40116940 PMCID: PMC11928343 DOI: 10.1007/s00018-025-05641-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/12/2025] [Accepted: 02/24/2025] [Indexed: 03/23/2025]
Abstract
Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients' single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.
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Affiliation(s)
- Ashwin Narayanan
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
- QV Bioelectronics Ltd., 21LGA, Alderley Park, Nether Alderley, Cheshire, SK10 4TG, UK
| | - Mirca S Saurty-Seerunghen
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, USA
| | - Jessica Michieletto
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
| | - Virgile Delaunay
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
| | - Arnaud Bruneel
- Service de Biochimie Métabolique et Cellulaire, Hôpital Bichat-Claude-Bernard, Paris, France
- INSERM UMR1193, Faculté de Pharmacie, Université Paris-Saclay, 91400, Orsay, France
| | - Thierry Dupré
- Service de Biochimie Métabolique et Cellulaire, Hôpital Bichat-Claude-Bernard, Paris, France
| | - Chris Ottolenghi
- France Paris Cité University, Imagine Institute -Inserm U1163, Metabolic Biochemistry Laboratory, Necker Hospital (APHP), Paris, France
| | - Clément Pontoizeau
- France Paris Cité University, Imagine Institute -Inserm U1163, Metabolic Biochemistry Laboratory, Necker Hospital (APHP), Paris, France
| | - Lucrezia Ciccone
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
| | - Andreas De La Vara
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
| | - Ahmed Idbaih
- Sorbonne Université, AP-HP, Institut du Cerveau -Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, DMU Neurosciences, Service de Neuro-Oncologie-Institut de Neurologie, F-75013, Paris, France
| | - Laurent Turchi
- Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM "Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity", 06108, Nice, France
| | - Thierry Virolle
- Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM "Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity", 06108, Nice, France
| | - Hervé Chneiweiss
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
| | - Marie-Pierre Junier
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France
| | - Elias A El-Habr
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Center for Neuroscience at Sorbonne Université, 7 Quai Saint-Bernard, 75005, Paris, France.
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Fu Z, Qiu H, Xu Y, Tan C, Wang H. Biological effects, properties and tissue engineering applications of polyhydroxyalkanoates: A review. Int J Biol Macromol 2025; 293:139281. [PMID: 39736299 DOI: 10.1016/j.ijbiomac.2024.139281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 12/10/2024] [Accepted: 12/27/2024] [Indexed: 01/01/2025]
Abstract
Polyhydroxyalkanoates (PHAs) are a group of polymers with a variety of monomers, which are extracted from microorganisms and plants. Due to its good biocompatibility, biodegradability, tunable mechanical property and piezoelectricity, PHAs have been widely used in biomedical fields, such as bone, cartilage, nerve, vascular and skin tissue engineering. This review focuses on the in vivo synthesis, metabolism and biological functions of PHA, and the applications of PHAs in the field of tissue engineering and commercial were also summarized and discussed. Moreover, this review hints the future perspective and research direction of PHA-based materials in the challenging field of tissue engineering. We hope that this review will catalyze the continued advancement and broadening of PHAs' applications in biomedicine.
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Affiliation(s)
- Zeyu Fu
- Beijing Joyinera biomaterial Technology Co., Ltd., Beijing, China
| | - He Qiu
- Beijing Joyinera biomaterial Technology Co., Ltd., Beijing, China; Department of Cosmetic and Plastic Surgery, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yuan Xu
- Beijing Joyinera biomaterial Technology Co., Ltd., Beijing, China
| | - Chang Tan
- Beijing Joyinera biomaterial Technology Co., Ltd., Beijing, China.
| | - Hang Wang
- Department of Cosmetic and Plastic Surgery, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Tahiliani H, Dhayalan A, Li MC, Hsieh HP, Coumar MS. Aldehyde dehydrogenases as drug targets for cancer: SAR and structural biology aspects for inhibitor design. Bioorg Chem 2025; 154:108019. [PMID: 39689509 DOI: 10.1016/j.bioorg.2024.108019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/20/2024] [Accepted: 11/28/2024] [Indexed: 12/19/2024]
Abstract
Aldehydes are organic compounds containing a carbonyl group found exogenously or produced by normal metabolic processes and their accumulation can lead to toxicity if not cleared. Aldehyde dehydrogenases (ALDHs) are NAD(P)+-dependent enzymes that catalyze the oxidation of such aldehydes and prevent their accumulation. Along with this primary detoxification function, the known 19 human isoforms of ALDHs, which act on different substrates, are also involved in various physiological and developmental processes. Functional alterations of ALDHs via mutations or expression levels cause various disease conditions, including many different cancer types like lung, ovarian, etc. These properties make this family of enzymes an ideal therapeutic and prognostic target for drug development. However, sequence similarities between the ALDH isoforms force the need to design inhibitors for a specific isoform using the differences in the substrate-binding sites of each protein. This has resulted in developing isoform-specific inhibitors, especially for ALDH1A1, ALDH2, and ALDH3A1, which are implicated in various cancers. In this review, we briefly outline the functional roles of the different isoforms of the ALDH family members, their role in cancer and discuss the various selective inhibitors that have been developed for the ALDH1A1 and ALDH3A1 enzymes, along with a detailed examination of the respective structure-activity relationship (SAR) studies available. From the available SAR and structural biology data, insights into the functional groups and interactions necessary to develop selective inhibitors for ALDH1A1 and ALDH3A1 are highlighted, which can act as a guide for developing more potent and selective inhibitors of ALDH isoforms.
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Affiliation(s)
- Himanshu Tahiliani
- Department of Bioinformatics, School of Life Scicnces, Pondicherry University, Pondicherry 605014, India
| | - Arunkumar Dhayalan
- Department of Biotechnology, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
| | - Mu-Chun Li
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC; Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan, ROC
| | - Hsing-Pang Hsieh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC; Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan, ROC; Department of Chemistry, National Tsing Hua University, Hsinchu City 300044, Taiwan, ROC
| | - Mohane Selvaraj Coumar
- Department of Bioinformatics, School of Life Scicnces, Pondicherry University, Pondicherry 605014, India.
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Junier MP, El-Habr EA. Emergence of the cell-matrix adhesion element ILK as a player in glioblastoma cell plasticity. Dev Cell 2024; 59:3189-3190. [PMID: 39689679 DOI: 10.1016/j.devcel.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 12/19/2024]
Abstract
Glioblastoma cells exhibit remarkable plasticity, enabling them to adapt to environmental cues and transition through various developmental-like states with distinct properties. In this issue of Developmental Cell, Loftus et al. identify ILK as an intrinsic regulator of glioblastoma cell transitions between progenitor-like and mesenchymal/astrocyte-like states.
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Affiliation(s)
- Marie-Pierre Junier
- Sorbonne université, CNRS, INSERM, Institut de Biologie Paris Seine, F-75005 Paris, France.
| | - Elias A El-Habr
- Sorbonne université, CNRS, INSERM, Institut de Biologie Paris Seine, F-75005 Paris, France
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Pan J, Yan D, Liang Y, Yang L, Hu C, Chen M. Bioinformatic analysis constructs an optimal prognostic index for survival-related variables (OPISV) based on whole-genome expression data in Glioblastoma. Int J Biol Macromol 2024; 282:137184. [PMID: 39505178 DOI: 10.1016/j.ijbiomac.2024.137184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/24/2024] [Accepted: 10/31/2024] [Indexed: 11/08/2024]
Abstract
PURPOSE Using clinical information and transcriptomic sequencing data from glioblastoma (GBM) patients in the TCGA database to perform gene-by-gene analysis that is aligned with individual patient characteristics and develop an optimal prognostic index of survival-related variables (OPISV) through iterative machine learning techniques to predict the prognosis of GBM patients. STUDY DESIGN The TCGA dataset was utilized as the training dataset, while two GEO datasets served as independent validation cohorts. Initially, survival analysis (p < 0.001***), differential gene expression analysis (p < 0.05*), and univariate Cox regression analysis (p < 0.05*) were employed to identify genes that are highly correlated with patient prognosis and exhibit significant differences in survival status. Subsequently, incorporating the non-excludable variable of age, a multivariate Cox regression analysis was performed in a stepwise manner to construct the OPISV. Finally, logistic and LASSO regressions were used to validate the association between the identified genes and patient survival. The OPISV performance is evaluated and its potential mechanisms are explored. RESULTS Age, CTSD, PTPRN, PTPRN2, NSUN5, DNAJC30 and SOX21 emerged as the optimal variables through multivariate Cox regression iterations. Further analysis characterized Age, PTPRN and DNAJC30 as independent prognostic risk factors for constructing OPISV, which is validated with external GEO datasets and GEPIA database. In OPISV_high populations, significantly upregulated GABAergic synapse function was exposed. Differential genes identified from gene clustering of the GABAergic synapse pathway and gene module highly correlated with GABAergic synapse in the WGCNA analysis are pointing unequivocally to the glioma progress. CONCLUSION OPISV is feasible for predicting patient survival, as it may serve as a potential mechanism underlying the involvement of GABAergic synapses in the progression of GBM.
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Affiliation(s)
- Junjia Pan
- Guangdong Second Provincial General Hospital, Guangzhou 510317, China; Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China; Department of Anesthesiology, the Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Dejun Yan
- Guangdong Second Provincial General Hospital, Guangzhou 510317, China; Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Yaoe Liang
- Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Lin Yang
- Department of Anesthesiology, the Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Rehabilitation Medicine Institute of Panyu District, Guangzhou, Guangdong, China
| | - Chun Hu
- Guangdong Second Provincial General Hospital, Guangzhou 510317, China; Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China.
| | - Meilan Chen
- Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
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Zhao W, Fang P, Lai C, Xu X, Wang Y, Liu H, Jiang H, Liu X, Liu J. Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis. Front Immunol 2024; 15:1366736. [PMID: 38566994 PMCID: PMC10985162 DOI: 10.3389/fimmu.2024.1366736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Background Ankylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins. Methods We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS. The plasma proteins were sourced from the UK Biobank Pharma Proteomics Project (UKB-PPP) database, encompassing GWAS data for 2,940 plasma proteins. Additionally, GWAS data for AS were extracted from the R9 version of the Finnish database, including 2,860 patients and 270,964 controls. The colocalization analysis was executed to identify shared causal variants between plasma proteins and AS. Finally, we examined the potential adverse effects of druggable proteins for AS therapy by conducting a phenome-wide association study (PheWAS) utilizing the extensive Finnish database in version R9, encompassing 2,272 phenotypes categorized into 46 groups. Results The findings revealed a positive genetic association between the predicted plasma levels of six proteins and an elevated risk of AS, while two proteins exhibited an inverse association with AS risk (P fdr < 0.05). Among these eight plasma proteins, colocalization analysis identified AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13 as shared variation with AS(PPH3+PPH4>0.8), suggesting that they represent potential direct targets for AS intervention. Further phenotype-wide association studies have shown some potential side effects of these six targets (P fdr < 0.05). Conclusion Our investigation examined the causal connections between six plasma proteins and AS, providing a comprehensive understanding of potential therapeutic targets.
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Affiliation(s)
- Wenlong Zhao
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Orthopedics, The Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, China
| | - Peng Fang
- Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Chengteng Lai
- Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xiaoyu Xu
- Department of Biology, Wake Forest University, North Carolina, NC, United States
| | - Yang Wang
- Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hao Liu
- Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hui Jiang
- Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xiaozhou Liu
- Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jun Liu
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Singh GK, Kumari B, Das N, Zaman K, Prasad P, Singh RB. Design, synthesis, molecular docking and pharmacological evaluation of some thiadiazole based nipecotic acid derivatives as a potential anticonvulsant and antidepressant agents. 3 Biotech 2024; 14:71. [PMID: 38362592 PMCID: PMC10864245 DOI: 10.1007/s13205-023-03897-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 12/18/2023] [Indexed: 02/17/2024] Open
Abstract
In our continuous effort to develop novel antiepileptic drug, a new series of nipecotic acid derivatives having1,3,4-thiadiazole nucleus were designed and synthesized. This study aims to improve the lipophilicity of nipecotic acid by attaching some lipophilic anchors like thiadiazole and substituted aryl acid derivatives. In our previous study, we noticed that the N-substituted oxadiazole derivative of nipecotic acid exhibited significant antiepileptic activity in the rodent model. The synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The anticonvulsant activity was evaluated by using the maximal electroshock-induced seizure model in rats (MES) and the subcutaneous pentylenetetrazol (scPTZ) test in mice. None of the compounds were found to be active in the MES model whereas compounds (TN2, TN9, TN12, TN13, and TN15) produced significant protection against the scPTZ-induced seizures model. The compounds showing antiepileptic activity were additionally evaluated for antidepressant activity by using the forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test, and learned helplessness test. All the molecules that showed anticonvulsant activity (TN2, TN9, TN12, TN13, and TN15), also exerted significant antidepressant effects in the animal models. The selected compounds were subjected to different toxicity studies. Compounds were found to have no neurotoxicity in the rota-rod test and devoid of hepatic and renal toxicity in 30 days repeated oral toxicity test. Further, a homology model was developed to perform the in-silico molecular docking and dynamics studies which revealed the similar binding of compound TN9 within the active binding pocket and were found to be the most potent anti-epileptic agent. The market expectation for newly developed antiepileptic thiadiazole-based nipecotic acid derivatives is significant, driven by their potential to offer improved therapeutic outcomes and reduced side effects, addressing a critical need in epilepsy treatment. These innovative compounds hold promise for meeting the demand for more effective and safer antiepileptic medications. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-023-03897-1.
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Affiliation(s)
- Gireesh Kumar Singh
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, Bihar 824236 India
| | - Bindu Kumari
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, Bihar 824236 India
| | - Nirupam Das
- Department of Pharmaceutical Science, SSMPS, Assam University, Silchar, Assam 788151 India
| | - Kamaruz Zaman
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - Pratibha Prasad
- Department of Neurology, All India Institute of Medical Sciences, Deoghar, Jharkhand 814142 India
| | - Ravi Bhushan Singh
- Institute of Pharmacy, Harischandra P.G. College, Bawanbeegha, Azamgarh Road, Varanasi, 221002 India
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Li H, Song C, Zhang Y, Liu G, Mi H, Li Y, Chen Z, Ma X, Zhang P, Cheng L, Peng P, Zhu H, Chen Z, Dong M, Chen S, Meng H, Xiao Q, Li H, Wu Q, Wang B, Zhang S, Shu K, Wan F, Guo D, Zhou W, Zhou L, Mao F, Rich JN, Yu X. Transgelin Promotes Glioblastoma Stem Cell Hypoxic Responses and Maintenance Through p53 Acetylation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305620. [PMID: 38087889 PMCID: PMC10870072 DOI: 10.1002/advs.202305620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Indexed: 02/17/2024]
Abstract
Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin-binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self-renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.
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Affiliation(s)
- Huan Li
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Chao Song
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yang Zhang
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Guohao Liu
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Hailong Mi
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Yachao Li
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Zhiye Chen
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Xiaoyu Ma
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Po Zhang
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Lidong Cheng
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Peng Peng
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Hongtao Zhu
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Zirong Chen
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Minhai Dong
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Sui Chen
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Hao Meng
- Intelligent Pathology InstituteThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230031China
| | - QunGen Xiao
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Honglian Li
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Qiulian Wu
- UPMC Hillman Cancer CenterDepartment of MedicineUniversity of Pittsburgh Medical CenterPittsburghPA15219USA
| | - Baofeng Wang
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Suojun Zhang
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Kai Shu
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Feng Wan
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Dongsheng Guo
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Wenchao Zhou
- Intelligent Pathology InstituteThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230031China
| | - Lin Zhou
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Feng Mao
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Jeremy N. Rich
- UPMC Hillman Cancer CenterDepartment of MedicineUniversity of Pittsburgh Medical CenterPittsburghPA15219USA
- Department of NeurologyUniversity of Pittsburgh School of MedicinePittsburghPA15213USA
| | - Xingjiang Yu
- Department of Histology and EmbryologySchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
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Lokumcu T, Iskar M, Schneider M, Helm D, Klinke G, Schlicker L, Bethke F, Müller G, Richter K, Poschet G, Phillips E, Goidts V. Proteomic, Metabolomic, and Fatty Acid Profiling of Small Extracellular Vesicles from Glioblastoma Stem-Like Cells and Their Role in Tumor Heterogeneity. ACS NANO 2024; 18:2500-2519. [PMID: 38207106 PMCID: PMC10811755 DOI: 10.1021/acsnano.3c11427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/13/2024]
Abstract
Glioblastoma is a deadly brain tumor for which there is no cure. The presence of glioblastoma stem-like cells (GSCs) contributes to the heterogeneous nature of the disease and makes developing effective therapies challenging. Glioblastoma cells have been shown to influence their environment by releasing biological nanostructures known as extracellular vesicles (EVs). Here, we investigated the role of GSC-derived nanosized EVs (<200 nm) in glioblastoma heterogeneity, plasticity, and aggressiveness, with a particular focus on their protein, metabolite, and fatty acid content. We showed that conditioned medium and small extracellular vesicles (sEVs) derived from cells of one glioblastoma subtype induced transcriptomic and proteomic changes in cells of another subtype. We found that GSC-derived sEVs are enriched in proteins playing a role in the transmembrane transport of amino acids, carboxylic acids, and organic acids, growth factor binding, and metabolites associated with amino acid, carboxylic acid, and sugar metabolism. This suggests a dual role of GSC-derived sEVs in supplying neighboring GSCs with valuable metabolites and proteins responsible for their transport. Moreover, GSC-derived sEVs were enriched in saturated fatty acids, while their respective cells were high in unsaturated fatty acids, supporting that the loading of biological cargos into sEVs is a highly regulated process and that GSC-derived sEVs could be sources of saturated fatty acids for the maintenance of glioblastoma cell metabolism. Interestingly, sEVs isolated from GSCs of the proneural and mesenchymal subtypes are enriched in specific sets of proteins, metabolites, and fatty acids, suggesting a molecular collaboration between transcriptionally different glioblastoma cells. In summary, this study revealed the complexity of GSC-derived sEVs and unveiled their potential contribution to tumor heterogeneity and critical cellular processes commonly deregulated in glioblastoma.
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Affiliation(s)
- Tolga Lokumcu
- Brain
Tumor Translational Targets, German Cancer
Research Center (DKFZ), Heidelberg 69120, Germany
- Faculty
of Biosciences, University of Heidelberg, Heidelberg 69120, Germany
| | - Murat Iskar
- Friedrich
Miescher Institute for Biomedical Research, Basel 4058, Switzerland
| | - Martin Schneider
- Proteomics
Core Facility, German Cancer Research Center
(DKFZ), Heidelberg 69120, Germany
| | - Dominic Helm
- Proteomics
Core Facility, German Cancer Research Center
(DKFZ), Heidelberg 69120, Germany
| | - Glynis Klinke
- Metabolomics
Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg 69120, Germany
| | - Lisa Schlicker
- Proteomics
Core Facility, German Cancer Research Center
(DKFZ), Heidelberg 69120, Germany
- Division
of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Frederic Bethke
- Brain
Tumor Translational Targets, German Cancer
Research Center (DKFZ), Heidelberg 69120, Germany
| | - Gabriele Müller
- Brain
Tumor Translational Targets, German Cancer
Research Center (DKFZ), Heidelberg 69120, Germany
| | - Karsten Richter
- Core
Facility Electron Microscopy, German Cancer
Research Center (DKFZ), Heidelberg 69120, Germany
| | - Gernot Poschet
- Metabolomics
Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg 69120, Germany
| | - Emma Phillips
- Brain
Tumor Translational Targets, German Cancer
Research Center (DKFZ), Heidelberg 69120, Germany
| | - Violaine Goidts
- Brain
Tumor Translational Targets, German Cancer
Research Center (DKFZ), Heidelberg 69120, Germany
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10
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Verissimo DCA, Camillo-Andrade AC, Santos MDM, Sprengel SL, Zanine SC, Borba LAB, Carvalho PC, da G. Fischer JDS. Proteomics reveals differentially regulated pathways when comparing grade 2 and 4 astrocytomas. PLoS One 2023; 18:e0290087. [PMID: 37967105 PMCID: PMC10651032 DOI: 10.1371/journal.pone.0290087] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 07/25/2023] [Indexed: 11/17/2023] Open
Abstract
Astrocytic tumors are known for their high progression capacity and high mortality rates; in this regard, proteins correlated to prognosis can aid medical conduct. Although several genetic changes related to progression from grade 2 to grade 4 astrocytoma are already known, mRNA copies do not necessarily correlate with protein abundance and therefore could shadow further comprehension about this tumor's biology. This motivates us to seek for complementary strategies to study tumor progression at the protein level. Here we compare the proteomic profile of biopsies from patients with grade 2 (diffuse, n = 6) versus grade 4 astrocytomas (glioblastomas, n = 10) using shotgun proteomics. Data analysis performed with PatternLab for proteomics identified 5,206 and 6,004 proteins in the 2- and 4-grade groups, respectively. Our results revealed seventy-four differentially abundant proteins (p < 0.01); we then shortlist those related to greater malignancy. We also describe molecular pathways distinctly activated in the two groups, such as differences in the organization of the extracellular matrix, decisive both in tumor invasiveness and in signaling for cell division, which, together with marked contrasts in energy metabolism, are determining factors in the speed of growth and dissemination of these neoplasms. The degradation pathways of GABA, enriched in the grade 2 group, is consistent with a favorable prognosis. Other functions such as platelet degranulation, apoptosis, and activation of the MAPK pathway were correlated to grade 4 tumors and, consequently, unfavorable prognoses. Our results provide an important survey of molecular pathways involved in glioma pathogenesis for these histopathological groups.
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Affiliation(s)
- Denildo C. A. Verissimo
- Laboratory for Structural and Computational Proteomics—Carlos Chagas Institute, Fiocruz Paraná, Curitiba, PR, Brazil
- Clinical Hospital of the Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Amanda C. Camillo-Andrade
- Laboratory for Structural and Computational Proteomics—Carlos Chagas Institute, Fiocruz Paraná, Curitiba, PR, Brazil
| | - Marlon D. M. Santos
- Laboratory for Structural and Computational Proteomics—Carlos Chagas Institute, Fiocruz Paraná, Curitiba, PR, Brazil
| | - Sergio L. Sprengel
- Clinical Hospital of the Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Simone C. Zanine
- Clinical Hospital of the Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Luis A. B. Borba
- Clinical Hospital of the Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Paulo C. Carvalho
- Laboratory for Structural and Computational Proteomics—Carlos Chagas Institute, Fiocruz Paraná, Curitiba, PR, Brazil
| | - Juliana de S. da G. Fischer
- Laboratory for Structural and Computational Proteomics—Carlos Chagas Institute, Fiocruz Paraná, Curitiba, PR, Brazil
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11
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Kaiser J, Nay K, Horne CR, McAloon LM, Fuller OK, Muller AG, Whyte DG, Means AR, Walder K, Berk M, Hannan AJ, Murphy JM, Febbraio MA, Gundlach AL, Scott JW. CaMKK2 as an emerging treatment target for bipolar disorder. Mol Psychiatry 2023; 28:4500-4511. [PMID: 37730845 PMCID: PMC10914626 DOI: 10.1038/s41380-023-02260-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 08/30/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023]
Abstract
Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.
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Affiliation(s)
- Jacqueline Kaiser
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
- St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia
- School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia
| | - Kevin Nay
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
| | - Christopher R Horne
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
| | - Luke M McAloon
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
- St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia
- School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia
| | - Oliver K Fuller
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
| | - Abbey G Muller
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
| | - Douglas G Whyte
- School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC, 3065, Australia
| | - Anthony R Means
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ken Walder
- The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, VIC, 3220, Australia
| | - Michael Berk
- The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, VIC, 3220, Australia
- Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, 3052, Australia
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Anthony J Hannan
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - James M Murphy
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Mark A Febbraio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
| | - Andrew L Gundlach
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia
- St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - John W Scott
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, 3052, Australia.
- St Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia.
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12
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Chen W, Yu H, Hao Y, Liu W, Wang R, Huang Y, Wu J, Feng L, Guan Y, Huang L, Qian K. Comprehensive Metabolic Fingerprints Characterize Neuromyelitis Optica Spectrum Disorder by Nanoparticle-Enhanced Laser Desorption/Ionization Mass Spectrometry. ACS NANO 2023; 17:19779-19792. [PMID: 37818994 DOI: 10.1021/acsnano.3c03765] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Timely screening of neuromyelitis optica spectrum disorder (NMOSD) and differential diagnosis from myelin oligodendrocyte glycoprotein associated disorder (MOGAD) are the keys to improving the quality of life of patients. Metabolic disturbance occurs with the development of NMOSD. Still, advanced tools are required to probe the metabolic phenotype of NMOSD. Here, we developed a fast nanoparticle-enhanced laser desorption/ionization mass spectrometry assay for multiplexing metabolic fingerprints (MFs) from trace plasma and cerebrospinal fluid (CSF) samples in 30 s. Machine learning of the plasma MFs achieved the timely screening of NMOSD from healthy donors with an area under receiver operator characteristic curve (AUROC) of 0.998, and it comprehensively revealed the dysregulated neurotransmitter and energy metabolisms. Combining comprehensive MFs from both plasma and CSF, we constructed an integrated panel for differential diagnosis of NMOSD versus MOGAD with an AUROC of 0.923. This approach demonstrated performance superior to that of human experts in classifying two diseases, especially in antibody assay-limited regions. Together, this approach provides an advanced nanomaterial-based tool for identifying vulnerable populations below the antibody threshold of aquaporin-4 positivity.
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Affiliation(s)
- Wei Chen
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
- State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering and Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Haojun Yu
- Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yong Hao
- Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wanshan Liu
- State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering and Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ruimin Wang
- State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering and Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yida Huang
- State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering and Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Jiao Wu
- State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering and Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Lei Feng
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai 201100, China
| | - Yangtai Guan
- Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Lin Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Kun Qian
- State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering and Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200030, China
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13
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Turchi L, Sakakini N, Saviane G, Polo B, Saurty-Seerunghen MS, Gabut M, Gouillou CA, Guerlais V, Pasquier C, Vignais ML, Almairac F, Chneiweiss H, Junier MP, Burel-Vandenbos F, Virolle T. CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3. Cancers (Basel) 2023; 15:5038. [PMID: 37894405 PMCID: PMC10605641 DOI: 10.3390/cancers15205038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/23/2023] [Accepted: 08/10/2023] [Indexed: 10/29/2023] Open
Abstract
Glioblastomas (GBs) are incurable brain tumors. The persistence of aggressive stem-like tumor cells after cytotoxic treatments compromises therapeutic efficacy, leading to GBM recurrence. Forcing the GBM cells to irreversibly abandon their aggressive stem-like phenotype may offer an alternative to conventional cytotoxic treatments. Here, we show that the RNA binding protein CELF2 is strongly expressed in mitotic and OLIG2-positive GBM cells, while it is downregulated in differentiated and non-mitotic cells by miR-199a-3p, exemplifying GBM intra-tumor heterogeneity. Using patient-derived cells and human GBM samples, we demonstrate that CELF2 plays a key role in maintaining the proliferative/OLIG2 cell phenotype with clonal and tumorigenic properties. Indeed, we show that CELF2 deficiency in patient-derived GSCs drastically reduced tumor growth in the brains of nude mice. We further show that CELF2 promotes TRIM28 and G9a expression, which drive a H3K9me3 epigenetic profile responsible for the silencing of the SOX3 gene. Thus, CELF2, which is positively correlated with OLIG2 and Ki67 expression in human GBM samples, is inversely correlated with SOX3 and miR-199a-3p. Accordingly, the invalidation of SOX3 in CELF2-deficient patient-derived cells rescued proliferation and OLIG2 expression. Finally, patients expressing SOX3 above the median level of expression tend to have a longer life expectancy. CELF2 is therefore a crucial target for the malignant potential of GBM and warrants attention when developing novel anticancer strategies.
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Affiliation(s)
- Laurent Turchi
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
- DRCI, CHU de Nice, 06107 Nice, France
| | - Nathalie Sakakini
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
| | - Gaelle Saviane
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
| | - Béatrice Polo
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
| | - Mirca Saras Saurty-Seerunghen
- CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France; (M.S.S.-S.); (H.C.); (M.-P.J.)
| | - Mathieu Gabut
- Stemness in Gliomas Laboratory, Cancer Initiation and Tumoral Cell Identity (CITI) Department, INSERM 1052, CNRS 5286, Centre Léon Bérard, 69008 Lyon, France;
- Cancer Research Center of Lyon 1, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France
| | | | - Vincent Guerlais
- CNRS, I3S, Université Côte d’Azur, 06560 Valbonne, France; (V.G.); (C.P.)
| | - Claude Pasquier
- CNRS, I3S, Université Côte d’Azur, 06560 Valbonne, France; (V.G.); (C.P.)
| | - Marie Luce Vignais
- CNRS, INSERM, Institut de Génomique Fonctionnelle, IGF, Université de Montpellier, 34090 Montpellier, France;
| | - Fabien Almairac
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
- Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, 06107 Nice, France
| | - Hervé Chneiweiss
- CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France; (M.S.S.-S.); (H.C.); (M.-P.J.)
| | - Marie-Pierre Junier
- CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France; (M.S.S.-S.); (H.C.); (M.-P.J.)
| | - Fanny Burel-Vandenbos
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
- Service d’Anatomopathologie, Hôpital Pasteur, CHU de Nice, 06107 Nice, France
| | - Thierry Virolle
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
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14
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Piperi C, Saurty-Seerunghen MS, Levidou G, Sepsa A, Trigka EA, Klonou A, Markouli M, Strepkos D, Spyropoulou A, Kanakoglou DS, Lakiotaki E, Karatrasoglou EA, Boviatsis E, El-Habr EA, Korkolopoulou P. Glioma Cells Expressing High Levels of ALDH5A1 Exhibit Enhanced Migration Transcriptional Signature in Patient Tumors. Neurotherapeutics 2023; 20:881-895. [PMID: 36976494 PMCID: PMC10275844 DOI: 10.1007/s13311-023-01354-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2023] [Indexed: 03/29/2023] Open
Abstract
Accumulating data shows that altered metabolic activity contributes to glioma development. Recently, modulation of SSADH (succinic semialdehyde dehydrogenase) expression, implicated in the catabolism of GABA neurotransmitter, was shown to impact glioma cell properties, such as proliferation, self-renewal and tumorigenicity. The purpose of this study was to investigate the clinical significance of SSADH expression in human gliomas. Using public single-cell RNA-sequencing data from glioma surgical resections, we initially grouped cancer cells according to ALDH5A1 (Aldehyde dehydrogenase 5 family member A1) expression, which encodes SSADH. Gene ontology enrichment analysis of genes differentially expressed between cancer cells expressing high or low levels of ALDH5A1, highlighted enrichment in genes implicated in cell morphogenesis and motility. In glioblastoma cell lines, ALDH5A1 knockdown inhibited cell proliferation, induced apoptosis and reduced their migratory potential. This was accompanied by a reduction in the mRNA levels of the adherens junction molecule ADAM-15 and deregulation in the expression of EMT biomarkers, with increased CDH1 and decreased vimentin mRNA levels. Evaluation of SSADH expression in a cohort of 95 gliomas using immunohistochemistry showed that SSADH expression was significantly elevated in cancer tissues compared to normal brain tissues, without any significant correlation with clinicopathological characteristics. In summary, our data show that SSADH is upregulated in glioma tissues irrespective of the histological grade and its expression sustains glioma cell motility.
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Affiliation(s)
- Christina Piperi
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Mirca S Saurty-Seerunghen
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Paris, France
| | - Georgia Levidou
- Department of Pathology, Medical School, Klinikum Nuremberg, Paracelsus University, Nuremberg, Germany
| | - Athanasia Sepsa
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens, Greece
| | - Eleni-Andriana Trigka
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens, Greece
| | - Alexia Klonou
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Mariam Markouli
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Strepkos
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Spyropoulou
- Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios S Kanakoglou
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens, Greece.
| | - Eleftheria Lakiotaki
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens, Greece
| | - Eleni A Karatrasoglou
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens, Greece
| | - Efstathios Boviatsis
- Department of Neurosurgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Elias A El-Habr
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Paris, France
| | - Penelope Korkolopoulou
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens, Greece.
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15
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Xia J, Li S, Liu S, Zhang L. Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets. MedComm (Beijing) 2023; 4:e195. [PMID: 36694633 PMCID: PMC9842923 DOI: 10.1002/mco2.195] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 01/18/2023] Open
Abstract
The family of aldehyde dehydrogenases (ALDHs) contains 19 isozymes and is involved in the oxidation of endogenous and exogenous aldehydes to carboxylic acids, which contributes to cellular and tissue homeostasis. ALDHs play essential parts in detoxification, biosynthesis, and antioxidants, which are of important value for cell proliferation, differentiation, and survival in normal body tissues. However, ALDHs are frequently dysregulated and associated with various diseases like Alzheimer's disease, Parkinson's disease, and especially solid tumors. Notably, the involvement of the ALDHs in tumor progression is responsible for the maintenance of the stem-cell-like phenotype, triggering rapid and aggressive clinical progressions. ALDHs have captured increasing attention as biomarkers for disease diagnosis and prognosis. Nevertheless, these require further longitudinal clinical studies in large populations for broad application. This review summarizes our current knowledge regarding ALDHs as potential biomarkers in tumors and several non-tumor diseases, as well as recent advances in our understanding of the functions and underlying molecular mechanisms of ALDHs in disease development. Finally, we discuss the therapeutic potential of ALDHs in diseases, especially in tumor therapy with an emphasis on their clinical implications.
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Affiliation(s)
- Jie Xia
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Siqin Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjingChina
| | - Lixing Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
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16
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Bikfalvi A, da Costa CA, Avril T, Barnier JV, Bauchet L, Brisson L, Cartron PF, Castel H, Chevet E, Chneiweiss H, Clavreul A, Constantin B, Coronas V, Daubon T, Dontenwill M, Ducray F, Enz-Werle N, Figarella-Branger D, Fournier I, Frenel JS, Gabut M, Galli T, Gavard J, Huberfeld G, Hugnot JP, Idbaih A, Junier MP, Mathivet T, Menei P, Meyronet D, Mirjolet C, Morin F, Mosser J, Moyal ECJ, Rousseau V, Salzet M, Sanson M, Seano G, Tabouret E, Tchoghandjian A, Turchi L, Vallette FM, Vats S, Verreault M, Virolle T. Challenges in glioblastoma research: focus on the tumor microenvironment. Trends Cancer 2023; 9:9-27. [PMID: 36400694 DOI: 10.1016/j.trecan.2022.09.005] [Citation(s) in RCA: 132] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 09/20/2022] [Accepted: 09/30/2022] [Indexed: 11/17/2022]
Abstract
Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels.
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Affiliation(s)
- Andreas Bikfalvi
- Bordeaux University, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, F-33600, Pessac, France.
| | - Cristine Alves da Costa
- Côte d'Azur University, INSERM, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Team "Laboratory of Excellence (LABEX) Distalz", F-06560 Nice, France
| | - Tony Avril
- Rennes University, Inserm U1242, Centre de Lutte contre le Cancer Eugène Marquis, F- 35000 Rennes, France
| | - Jean-Vianney Barnier
- Institute of Neuroscience Paris-Saclay, UMR9197, CNRS, Univ. Paris-Saclay, F-91191 Gif-sur-Yvette, France
| | - Luc Bauchet
- Montpellier University Medical Center, Department of Neurosurgery, INSERM U1191, F-34090 Montpellier, France
| | - Lucie Brisson
- Bordeaux University, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, F-33600, Pessac, France
| | | | - Hélène Castel
- Normandie University, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), F-76000 Rouen, France
| | - Eric Chevet
- Rennes University, Inserm U1242, Centre de Lutte contre le Cancer Eugène Marquis, F- 35000 Rennes, France
| | - Hervé Chneiweiss
- Sorbonne University, CNRS UMR8246, Inserm U1130, IBPS-Neuroscience Paris Seine, F- 75005 Paris, France
| | - Anne Clavreul
- Angers University, CHU d'Angers, CRCINA, F-49000 Angers, France
| | - Bruno Constantin
- Poitiers University, CNRS UMR 6041, Laboratory Channels & Connexins in Cancers and Cell Stemness, F-86000 Poitiers, France
| | - Valérie Coronas
- Poitiers University, CNRS UMR 6041, Laboratory Channels & Connexins in Cancers and Cell Stemness, F-86000 Poitiers, France
| | - Thomas Daubon
- Bordeaux University, CNRS, IBGC, UMR 5095, F-33 077 Bordeaux, France
| | - Monique Dontenwill
- Strasbourg University, Laboratoire de Bioimagerie et Pathologie, UMR7021 CNRS, F-67401 Illkirch-Graffenstaden, France
| | - Francois Ducray
- Lyon I University, Cancer Research Centre of Lyon (CRCL) INSERM 1052&CNRS UMR5286, Centre Léon Bérard, Lyon 69008, France., F-69622 Villeurbanne, France
| | - Natacha Enz-Werle
- Strasbourg University, Laboratoire de Bioimagerie et Pathologie, UMR7021 CNRS, F-67401 Illkirch-Graffenstaden, France
| | - Dominique Figarella-Branger
- Aix-Marseille University, Service d'Anatomie Pathologique et de Neuropathologie, Hôpital de la Timone, F-13385 Marseille, France
| | - Isabelle Fournier
- Lille University, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000 Lille, France
| | - Jean-Sébastien Frenel
- Normandie University, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), F-76000 Rouen, France
| | - Mathieu Gabut
- Lyon I University, Cancer Research Centre of Lyon (CRCL) INSERM 1052&CNRS UMR5286, Centre Léon Bérard, Lyon 69008, France., F-69622 Villeurbanne, France
| | - Thierry Galli
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, GHU PARIS Psychiatrie & Neurosciences, F-75014 Paris, France
| | - Julie Gavard
- CRCI2NA, INSERM U1307, CNRS UMR6075, Nantes Universite, 44007 Nantes, France
| | - Gilles Huberfeld
- College de France, Center for Interdisciplinary Research in Biology (CIRB), CNRS, INSERM, Université PSL, Paris 75005, France
| | - Jean-Philippe Hugnot
- Montpellier University, Institut de Génomique Fonctionnelle, CNRS, INSERM, F-34094 Montpellier, France
| | - Ahmed Idbaih
- Sorbonne University, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, F-75013, Paris, France
| | - Marie-Pierre Junier
- Sorbonne University, CNRS UMR8246, Inserm U1130, IBPS-Neuroscience Paris Seine, F- 75005 Paris, France
| | - Thomas Mathivet
- Bordeaux University, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, F-33600, Pessac, France
| | - Philippe Menei
- Angers University, CHU d'Angers, CRCINA, F-49000 Angers, France
| | - David Meyronet
- Institute of Neuropathology, Hospices Civils de Lyon, F-69008, Lyon, France
| | - Céline Mirjolet
- Centre Georges-François Leclerc, UNICANCER, Dijon, France. Inserm U1231, Equipe Cadir, F-21000 Dijon, France
| | - Fabrice Morin
- Normandie University, INSERM U1239, DC2N, Institute for Research and Innovation in Biomedicine (IRIB), F-76000 Rouen, France
| | - Jean Mosser
- Rennes University, Inserm U1242, Centre de Lutte contre le Cancer Eugène Marquis, F- 35000 Rennes, France
| | - Elisabeth Cohen-Jonathan Moyal
- Institut Claudius Regaud, NSERM 1037, CRCT Team RADOPT, Département de Radiothérapie, IUCT-Oncopole, F-31100 Toulouse, France
| | - Véronique Rousseau
- Institute of Neuroscience Paris-Saclay, UMR9197, CNRS, Univ. Paris-Saclay, F-91191 Gif-sur-Yvette, France
| | - Michel Salzet
- Lille University, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000 Lille, France
| | - Marc Sanson
- Sorbonne University, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, F-75013, Paris, France
| | - Giorgio Seano
- Curie Institute Research Center, Tumor Microenvironment Laboratory, PSL Research University, Inserm U1021, CNRS UMR3347, F-91898 Orsay, France
| | - Emeline Tabouret
- Aix-Marseille University, CNRS, INP, Inst Neurophysiopathol, F-13005 Marseille, France
| | - Aurélie Tchoghandjian
- Aix-Marseille University, CNRS, INP, Inst Neurophysiopathol, F-13005 Marseille, France
| | - Laurent Turchi
- Côte D'Azur University, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM "Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity", F-06108 Nice, France
| | - Francois M Vallette
- CRCI2NA, INSERM U1307, CNRS UMR6075, Nantes Universite, 44007 Nantes, France
| | - Somya Vats
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, GHU PARIS Psychiatrie & Neurosciences, F-75014 Paris, France
| | - Maité Verreault
- Sorbonne University, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, F-75013, Paris, France
| | - Thierry Virolle
- Côte D'Azur University, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM "Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity", F-06108 Nice, France
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17
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Jiang H, Sun Z, Li F, Chen Q. Prognostic value of γ‐aminobutyric acidergic synapse-associated signature for lower-grade gliomas. Front Immunol 2022; 13:983569. [PMID: 36405708 PMCID: PMC9668880 DOI: 10.3389/fimmu.2022.983569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
Background Synapse-associated proteins (SAPs) play important roles in central nervous system (CNS) tumors. Recent studies have reported that γ-aminobutyric acidergic (GABAergic) synapses also play critical roles in the development of gliomas. However, biomarkers of GABAergic synapses in low-grade gliomas (LGGs) have not yet been reported. Methods mRNA data from normal brain tissue and gliomas were obtained from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, respectively. A validation dataset was also obtained from the Chinese Glioma Genome Atlas (CGGA) database. The expression patterns of GABAergic synapse-related genes (GSRGs) were evaluated with difference analysis in LGGs. Then, a GABAergic synapse-related risk signature (GSRS) was constructed with least absolute shrinkage and selection operator (LASSO) Cox regression analysis. According to the expression value and coefficients of identified GSRGs, the risk scores of all LGG samples were calculated. Univariate and multivariate Cox regression analyses were conducted to evaluate related risk scores for prognostic ability. Correlations between characteristics of the tumor microenvironment (TME) and risk scores were explored with single-sample gene set enrichment analysis (ssGSEA) and immunity profiles in LGGs. The GSRS-related pathways were investigated by gene set variation analysis (GSVA). Real-time PCR and the Human Protein Atlas (HPA) database were applied to explore related expression of hub genes selected in the GSRS. Results Compared with normal brain samples, 25 genes of 31 GSRGs were differentially expressed in LGG samples. A constructed five-gene GSRS was related to clinicopathological features and prognosis of LGGs by the LASSO algorithm. It was shown that the risk score level was positively related to the infiltrating level of native CD4 T cells and activated dendritic cells. GSVA identified several cancer-related pathways associated with the GSRS, such as P53 pathways and the JAK-STAT signaling pathway. Additionally, CA2, PTEN, OXTR, and SLC6A1 (hub genes identified in the GSRS) were regarded as the potential predictors in LGGs. Conclusion A new five-gene GSRS was identified and verified by bioinformatics methods. The GSRS provides a new perspective in LGG that may contribute to more accurate prediction of prognosis of LGGs.
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Affiliation(s)
- Hongxiang Jiang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhiqiang Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Fei Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- *Correspondence: Fei Li, ; Qianxue Chen,
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- *Correspondence: Fei Li, ; Qianxue Chen,
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18
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Saurty-Seerunghen MS, Daubon T, Bellenger L, Delaunay V, Castro G, Guyon J, Rezk A, Fabrega S, Idbaih A, Almairac F, Burel-Vandenbos F, Turchi L, Duplus E, Virolle T, Peyrin JM, Antoniewski C, Chneiweiss H, El-Habr EA, Junier MP. Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase. Cell Death Dis 2022. [PMID: 36310164 DOI: 10.1038/s41419-022-05358-8.pmid:36310164;pmcid:pmc9618559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients' glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients' tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients' tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients' tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.
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Affiliation(s)
- Mirca S Saurty-Seerunghen
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Thomas Daubon
- CNRS UMR5095, Inserm U1029, Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, Team Bioenergetics and dynamics of mitochondria, Bordeaux, France
| | - Léa Bellenger
- ARTbio Bioinformatics Analysis Facility, Sorbonne Université, CNRS, Institut de Biologie Paris Seine, Paris, France
| | - Virgile Delaunay
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Gloria Castro
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Joris Guyon
- Inserm U1312, Université de Bordeaux, Pessac, France
| | - Ahmed Rezk
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Sylvie Fabrega
- Plateforme Vecteurs Viraux et Transfert de Gènes, Université Paris Descartes-Structure Fédérative de Recherche Necker, CNRS UMS3633, Inserm US24, Paris, France
| | - Ahmed Idbaih
- CNRS UMR 7225, Inserm U1127, Sorbonne Université, Institut du Cerveau et de la Moelle épinière, Paris, France
| | - Fabien Almairac
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France
- Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, Nice, 06107, France
| | - Fanny Burel-Vandenbos
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France
- Service d'anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice, 06107, France
| | - Laurent Turchi
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France
- DRCI, CHU de Nice, Nice, 06107, France
| | - Eric Duplus
- CNRS UMR8256, INSERM ERL1164, Sorbonne Université, Biological adaptation and aging-IBPS Laboratory, Team Integrated cellular aging and inflammation, Paris, France
| | - Thierry Virolle
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France
| | - Jean-Michel Peyrin
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Axonal degeneration and regeneration, Paris, France
| | - Christophe Antoniewski
- ARTbio Bioinformatics Analysis Facility, Sorbonne Université, CNRS, Institut de Biologie Paris Seine, Paris, France
| | - Hervé Chneiweiss
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Elias A El-Habr
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France.
| | - Marie-Pierre Junier
- CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France.
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19
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Saurty-Seerunghen MS, Daubon T, Bellenger L, Delaunay V, Castro G, Guyon J, Rezk A, Fabrega S, Idbaih A, Almairac F, Burel-Vandenbos F, Turchi L, Duplus E, Virolle T, Peyrin JM, Antoniewski C, Chneiweiss H, El-Habr EA, Junier MP. Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase. Cell Death Dis 2022; 13:913. [PMID: 36310164 PMCID: PMC9618559 DOI: 10.1038/s41419-022-05358-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 01/23/2023]
Abstract
Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients' glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients' tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients' tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients' tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.
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Affiliation(s)
- Mirca S. Saurty-Seerunghen
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Thomas Daubon
- grid.462122.10000 0004 1795 2841CNRS UMR5095, Inserm U1029, Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, Team Bioenergetics and dynamics of mitochondria, Bordeaux, France
| | - Léa Bellenger
- grid.503253.20000 0004 0520 7190ARTbio Bioinformatics Analysis Facility, Sorbonne Université, CNRS, Institut de Biologie Paris Seine, Paris, France
| | - Virgile Delaunay
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Gloria Castro
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Joris Guyon
- grid.412041.20000 0001 2106 639XInserm U1312, Université de Bordeaux, Pessac, France
| | - Ahmed Rezk
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Sylvie Fabrega
- grid.508487.60000 0004 7885 7602Plateforme Vecteurs Viraux et Transfert de Gènes, Université Paris Descartes-Structure Fédérative de Recherche Necker, CNRS UMS3633, Inserm US24, Paris, France
| | - Ahmed Idbaih
- grid.425274.20000 0004 0620 5939CNRS UMR 7225, Inserm U1127, Sorbonne Université, Institut du Cerveau et de la Moelle épinière, Paris, France
| | - Fabien Almairac
- grid.461605.0Université Côte D’Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France ,grid.464719.90000 0004 0639 4696Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, Nice, 06107 France
| | - Fanny Burel-Vandenbos
- grid.461605.0Université Côte D’Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France ,grid.464719.90000 0004 0639 4696Service d’anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice, 06107 France
| | - Laurent Turchi
- grid.461605.0Université Côte D’Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France ,grid.410528.a0000 0001 2322 4179DRCI, CHU de Nice, Nice, 06107 France
| | - Eric Duplus
- grid.462844.80000 0001 2308 1657CNRS UMR8256, INSERM ERL1164, Sorbonne Université, Biological adaptation and aging-IBPS Laboratory, Team Integrated cellular aging and inflammation, Paris, France
| | - Thierry Virolle
- grid.461605.0Université Côte D’Azur, CNRS, INSERM, Institut de Biologie Valrose, Team INSERM Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity, Nice, France
| | - Jean-Michel Peyrin
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Axonal degeneration and regeneration, Paris, France
| | - Christophe Antoniewski
- grid.503253.20000 0004 0520 7190ARTbio Bioinformatics Analysis Facility, Sorbonne Université, CNRS, Institut de Biologie Paris Seine, Paris, France
| | - Hervé Chneiweiss
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Elias A. El-Habr
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
| | - Marie-Pierre Junier
- grid.462844.80000 0001 2308 1657CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France
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20
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Ruiz-Rodado V, Dowdy T, Lita A, Kramp T, Zhang M, Shuboni-Mulligan D, Herold-Mende C, Armstrong TS, Gilbert MR, Camphausen K, Larion M. Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model. Front Oncol 2022; 12:979537. [DOI: 10.3389/fonc.2022.979537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13C-tracing experiments were performed at end-point utilizing [U-13C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.
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Neurotransmitters: Potential Targets in Glioblastoma. Cancers (Basel) 2022; 14:cancers14163970. [PMID: 36010960 PMCID: PMC9406056 DOI: 10.3390/cancers14163970] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/12/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Aiming to discover potential treatments for GBM, this review connects emerging research on the roles of neurotransmitters in the normal neural and the GBM microenvironments and sheds light on the prospects of their application in the neuropharmacology of GBM. Conventional therapy is blamed for its poor effect, especially in inhibiting tumor recurrence and invasion. Facing this dilemma, we focus on neurotransmitters that modulate GBM initiation, progression and invasion, hoping to provide novel therapy targeting GBM. By analyzing research concerning GBM therapy systematically and scientifically, we discover increasing insights into the regulatory effects of neurotransmitters, some of which have already shown great potential in research in vivo or in vitro. After that, we further summarize the potential drugs in correlation with previously published research. In summary, it is worth expecting that targeting neurotransmitters could be a promising novel pharmacological approach for GBM treatment. Abstract For decades, glioblastoma multiforme (GBM), a type of the most lethal brain tumor, has remained a formidable challenge in terms of its treatment. Recently, many novel discoveries have underlined the regulatory roles of neurotransmitters in the microenvironment both physiologically and pathologically. By targeting the receptors synaptically or non-synaptically, neurotransmitters activate multiple signaling pathways. Significantly, many ligands acting on neurotransmitter receptors have shown great potential for inhibiting GBM growth and development, requiring further research. Here, we provide an overview of the most novel advances concerning the role of neurotransmitters in the normal neural and the GBM microenvironments, and discuss potential targeted drugs used for GBM treatment.
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22
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Kishk A, Pacheco MP, Heurtaux T, Sinkkonen L, Pang J, Fritah S, Niclou SP, Sauter T. Review of Current Human Genome-Scale Metabolic Models for Brain Cancer and Neurodegenerative Diseases. Cells 2022; 11:2486. [PMID: 36010563 PMCID: PMC9406599 DOI: 10.3390/cells11162486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/28/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Brain disorders represent 32% of the global disease burden, with 169 million Europeans affected. Constraint-based metabolic modelling and other approaches have been applied to predict new treatments for these and other diseases. Many recent studies focused on enhancing, among others, drug predictions by generating generic metabolic models of brain cells and on the contextualisation of the genome-scale metabolic models with expression data. Experimental flux rates were primarily used to constrain or validate the model inputs. Bi-cellular models were reconstructed to study the interaction between different cell types. This review highlights the evolution of genome-scale models for neurodegenerative diseases and glioma. We discuss the advantages and drawbacks of each approach and propose improvements, such as building bi-cellular models, tailoring the biomass formulations for glioma and refinement of the cerebrospinal fluid composition.
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Affiliation(s)
- Ali Kishk
- Department of Life Sciences and Medicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
| | - Maria Pires Pacheco
- Department of Life Sciences and Medicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
| | - Tony Heurtaux
- Department of Life Sciences and Medicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
- Luxembourg Center of Neuropathology, L-3555 Dudelange, Luxembourg
| | - Lasse Sinkkonen
- Department of Life Sciences and Medicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
| | - Jun Pang
- Department of Computer Science, University of Luxembourg, L-4364 Esch-sur-Alzette, Luxembourg
| | - Sabrina Fritah
- NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health, Department of Cancer Research, L-1526 Luxembourg, Luxembourg
| | - Simone P. Niclou
- NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health, Department of Cancer Research, L-1526 Luxembourg, Luxembourg
| | - Thomas Sauter
- Department of Life Sciences and Medicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
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Ntafoulis I, Koolen SLW, Leenstra S, Lamfers MLM. Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma. Cancers (Basel) 2022; 14:3705. [PMID: 35954371 PMCID: PMC9367381 DOI: 10.3390/cancers14153705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 12/10/2022] Open
Abstract
Glioblastoma (GBM) remains one of the most difficult tumors to treat. The mean overall survival rate of 15 months and the 5-year survival rate of 5% have not significantly changed for almost 2 decades. Despite progress in understanding the pathophysiology of the disease, no new effective treatments to combine with radiation therapy after surgical tumor debulking have become available since the introduction of temozolomide in 1999. One of the main reasons for this is the scarcity of compounds that cross the blood-brain barrier (BBB) and reach the brain tumor tissue in therapeutically effective concentrations. In this review, we focus on the role of the BBB and its importance in developing brain tumor treatments. Moreover, we discuss drug repurposing, a drug discovery approach to identify potential effective candidates with optimal pharmacokinetic profiles for central nervous system (CNS) penetration and that allows rapid implementation in clinical trials. Additionally, we provide an overview of repurposed candidate drug currently being investigated in GBM at the preclinical and clinical levels. Finally, we highlight the importance of phase 0 trials to confirm tumor drug exposure and we discuss emerging drug delivery technologies as an alternative route to maximize therapeutic efficacy of repurposed candidate drug.
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Affiliation(s)
- Ioannis Ntafoulis
- Brain Tumor Center, Department of Neurosurgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (I.N.); (S.L.)
| | - Stijn L. W. Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands;
- Department of Hospital Pharmacy, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Sieger Leenstra
- Brain Tumor Center, Department of Neurosurgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (I.N.); (S.L.)
| | - Martine L. M. Lamfers
- Brain Tumor Center, Department of Neurosurgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (I.N.); (S.L.)
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Liu Y, Cui DX, Pan Y, Yu SH, Zheng LW, Wan M. Metabolic-epigenetic nexus in regulation of stem cell fate. World J Stem Cells 2022; 14:490-502. [PMID: 36157525 PMCID: PMC9350619 DOI: 10.4252/wjsc.v14.i7.490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/31/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Stem cell fate determination is one of the central questions in stem cell biology, and although its regulation has been studied at genomic and proteomic levels, a variety of biological activities in cells occur at the metabolic level. Metabolomics studies have established the metabolome during stem cell differentiation and have revealed the role of metabolites in stem cell fate determination. While metabolism is considered to play a biological regulatory role as an energy source, recent studies have suggested the nexus between metabolism and epigenetics because several metabolites function as cofactors and substrates in epigenetic mechanisms, including histone modification, DNA methylation, and microRNAs. Additionally, the epigenetic modification is sensitive to the dynamic metabolites and consequently leads to changes in transcription. The nexus between metabolism and epigenetics proposes a novel stem cell-based therapeutic strategy through manipulating metabolites. In the present review, we summarize the possible nexus between metabolic and epigenetic regulation in stem cell fate determination, and discuss the potential preventive and therapeutic strategies via targeting metabolites.
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Affiliation(s)
- Yi Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Di-Xin Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yue Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Han Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Wei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mian Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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Cruz JVR, Batista C, Afonso BDH, Alexandre-Moreira MS, Dubois LG, Pontes B, Moura Neto V, Mendes FDA. Obstacles to Glioblastoma Treatment Two Decades after Temozolomide. Cancers (Basel) 2022; 14:cancers14133203. [PMID: 35804976 PMCID: PMC9265128 DOI: 10.3390/cancers14133203] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/17/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Glioblastomas are the most common and aggressive brain tumors in adults, with a median survival of 15 months. Treatment is surgical removal, followed by chemotherapy and/or radiotherapy. Current chemotherapeutics do not kill all the tumor cells and some cells survive, leading to the appearance of a new tumor resistant to the treatment. These treatment-resistant cells are called tumor stem cells. In addition, glioblastoma cells have a high capacity for migration, forming new tumors in areas distant from the original tumor. Studies are now focused on understanding the molecular mechanisms of chemoresistance and controlling drug entry into the brain to improve drug performance. Another promising therapeutic approach is the use of viruses that specifically destroy glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological features of glioblastoma and the therapeutic targets that are currently under study for new clinical trials. Abstract Glioblastomas are considered the most common and aggressive primary brain tumor in adults, with an average of 15 months’ survival rate. The treatment is surgery resection, followed by chemotherapy with temozolomide, and/or radiotherapy. Glioblastoma must have wild-type IDH gene and some characteristics, such as TERT promoter mutation, EGFR gene amplification, microvascular proliferation, among others. Glioblastomas have great heterogeneity at cellular and molecular levels, presenting distinct phenotypes and diversified molecular signatures in each tumor mass, making it difficult to define a specific therapeutic target. It is believed that the main responsibility for the emerge of these distinct patterns lies in subcellular populations of tumor stem cells, capable of tumor initiation and asymmetric division. Studies are now focused on understanding molecular mechanisms of chemoresistance, the tumor microenvironment, due to hypoxic and necrotic areas, cytoskeleton and extracellular matrix remodeling, and in controlling blood brain barrier permeabilization to improve drug delivery. Another promising therapeutic approach is the use of oncolytic viruses that are able to destroy specifically glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological characteristics of glioblastoma and the cutting-edge therapeutic targets that are currently under study for promising new clinical trials.
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Affiliation(s)
- João Victor Roza Cruz
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
| | - Carolina Batista
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
| | - Bernardo de Holanda Afonso
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
- Instituto Estadual do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro 20231-092, Brazil
| | - Magna Suzana Alexandre-Moreira
- Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Campus A.C. Simões, Avenida Lourival Melo Mota, Maceio 57072-970, Brazil;
| | - Luiz Gustavo Dubois
- UFRJ Campus Duque de Caxias Professor Geraldo Cidade, Rodovia Washington Luiz, n. 19.593, km 104.5, Santa Cruz da Serra, Duque de Caxias 25240-005, Brazil;
| | - Bruno Pontes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
| | - Vivaldo Moura Neto
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
- Instituto Estadual do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro 20231-092, Brazil
| | - Fabio de Almeida Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
- Correspondence:
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Brągiel-Pieczonka A, Lipka G, Stapińska-Syniec A, Czyżewski M, Żybura-Broda K, Sobstyl M, Rylski M, Grabiec M. The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas. Front Oncol 2022; 12:621460. [PMID: 35494033 PMCID: PMC9047681 DOI: 10.3389/fonc.2022.621460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 03/17/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are the most common primary malignant intracranial brain tumors. Their proliferative and invasive behavior is controlled by various epigenetic mechanisms. 5-hydroxymethylcytosine (5-hmC) is one of the epigenetic DNA modifications that employs ten-eleven translocation (TET) enzymes to its oxidation. Previous studies demonstrated altered expression of 5-hmC across gliomagenesis. However, its contribution to the initiation and progression of human gliomas still remains unknown. To characterize the expression profiles of 5-hmC and TET in human glioma samples we used the EpiJET 5-hmC and 5-mC Analysis Kit, quantitative real-time PCR, and Western blot analysis. A continuous decline of 5-hmC levels was observed in solid tissue across glioma grades. However, in glioblastoma (GBM), we documented uncommon heterogeneity in 5-hmC expression. Further analysis showed that the levels of TET proteins, but not their transcripts, may influence the 5-hmC abundance in GBM. Early tumor-related biomarkers may also be provided by the study of aberrant DNA hydroxymethylation in the blood of glioma patients. Therefore, we explored the patterns of TET transcripts in plasma samples and we found that their profiles were variously regulated, with significant value for TET2. The results of our study confirmed that DNA hydroxymethylation is an important mechanism involved in the pathogenesis of gliomas, with particular reference to glioblastoma. Heterogeneity of 5-hmC and TET proteins expression across GBM may provide novel insight into define subtype-specific patterns of hydroxymethylome, and thus help to interpret the heterogeneous outcomes of patients with the same disease.
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Affiliation(s)
| | - Gabriela Lipka
- Department of Clinical Cytology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | | | - Michał Czyżewski
- Department of Neurosurgery, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Katarzyna Żybura-Broda
- Department of Clinical Cytology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Michał Sobstyl
- Department of Neurosurgery, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Marcin Rylski
- Department of Clinical Cytology, Centre of Postgraduate Medical Education, Warsaw, Poland.,Department of Radiology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Marta Grabiec
- Department of Clinical Cytology, Centre of Postgraduate Medical Education, Warsaw, Poland
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Pienkowski T, Kowalczyk T, Garcia-Romero N, Ayuso-Sacido A, Ciborowski M. Proteomics and metabolomics approach in adult and pediatric glioma diagnostics. Biochim Biophys Acta Rev Cancer 2022; 1877:188721. [PMID: 35304294 DOI: 10.1016/j.bbcan.2022.188721] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/26/2022]
Abstract
The diagnosis of glioma is mainly based on imaging methods that do not distinguish between stage and subtype prior to histopathological analysis. Patients with gliomas are generally diagnosed in the symptomatic stage of the disease. Additionally, healing scar tissue may be mistakenly identified based on magnetic resonance imaging (MRI) as a false positive tumor recurrence in postoperative patients. Current knowledge of molecular alterations underlying gliomagenesis and identification of tumoral biomarkers allow for their use as discriminators of the state of the organism. Moreover, a multiomics approach provides the greatest spectrum and the ability to track physiological changes and can serve as a minimally invasive method for diagnosing asymptomatic gliomas, preceding surgery and allowing for the initiation of prophylactic treatment. It is important to create a vast biomarker library for adults and pediatric patients due to their metabolic differences. This review focuses on the most promising proteomic, metabolomic and lipidomic glioma biomarkers, their pathways, the interactions, and correlations that can be considered characteristic of tumor grade or specific subtype.
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Affiliation(s)
- Tomasz Pienkowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland.
| | - Tomasz Kowalczyk
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland; Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland
| | - Noemi Garcia-Romero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
| | - Angel Ayuso-Sacido
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain; Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain; Faculty of Medicine, Universidad Francisco de Vitoria, 28223 Madrid, Spain
| | - Michal Ciborowski
- Clinical Research Centre, Medical University of Bialystok, M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
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Mechanism of Baclofen Inhibiting the Proliferation and Metastasis of GBM by Regulating YAP. J CHEM-NY 2021. [DOI: 10.1155/2021/2753571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
This study explores the effect of baclofen on the malignant phenotype of glioblastoma (GBM) and the growth of xenograft tumors and investigates the related mechanisms, aiming to reveal the effect of baclofen on the occurrence and development of GBM. The development of new therapeutic drugs for GBM lays a theoretical and experimental foundation. Research results show that baclofen could inhibit GBM cell proliferation and migration and promote GBM cell apoptosis; baclofen dose- and time-dependently could induce GBM cell YAP phosphorylation. YAP participated in the effect of baclofen on GBM cell proliferation and migration inhibition. Baclofen induced YAP phosphorylation in GBM cells through the GABABR2-Gs-Lats1/2 signaling pathway. Baclofen could inhibit the expression of survivin and Bcl2. Baclofen inhibits subcutaneous tumors by inducing YAP phosphorylation in vivo.
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Guo DZ, Huang A, Wang YP, Cao Y, Fan J, Yang XR, Zhou J. Development of an Eight-gene Prognostic Model for Overall Survival Prediction in Patients with Hepatocellular Carcinoma. J Clin Transl Hepatol 2021; 9:898-908. [PMID: 34966653 PMCID: PMC8666363 DOI: 10.14218/jcth.2020.00152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 03/27/2021] [Accepted: 04/11/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND AND AIMS The overall survival (OS) of hepatocellular carcinoma (HCC) remains dismal. Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision. This study aimed to develop a prognostic gene model for HCC. METHODS GSE14520 was retrieved as a training set to identify differential expressed genes (DEGs) between tumor and adjacent liver tissues in HCC patients with different OS. A DEG-based prognostic model was then constructed and the TCGA-LIHC and ICGC-LIRI datasets were used to validate the model. The area under the receiver operating characteristic curve (AUC) and hazard ratio (HR) of the model for OS were calculated. A model-based nomogram was established and verified. RESULTS In the training set, differential expression analysis identified 80 genes dysregulated in oxidation-reduction and metabolism regulation. After univariate Cox and LASSO regression, eight genes (LPCAT1, DHRS1, SORBS2, ALDH5A1, SULT1C2, SPP1, HEY1 and GOLM1) were selected to build the prognostic model. The AUC for 1-, 3- and 5-year OS were 0.779, 0.736, 0.754 in training set and 0.693, 0.689, 0.693 in the TCGA-LIHC validation set, respectively. The AUC for 1- and 3-year OS were 0.767 and 0.705 in the ICGC-LIRI validation set. Multivariate analysis confirmed the model was an independent prognostic factor (training set: HR=4.422, p<0.001; TCGA-LIHC validation set: HR=2.561, p<0.001; ICGC-LIRI validation set: HR=3.931, p<0.001). Furthermore, a nomogram combining the model and AJCC stage was established and validated, showing increased OS predictive efficacy compared with the prognostic model (p=0.035) or AJCC stage (p<0.001). CONCLUSIONS Our eight-gene prognostic model and the related nomogram represent as reliable prognostic tools for OS prediction in HCC patients.
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Affiliation(s)
- De-Zhen Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu-Peng Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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Maravat M, Bertrand M, Landon C, Fayon F, Morisset-Lopez S, Sarou-Kanian V, Decoville M. Complementary Nuclear Magnetic Resonance-Based Metabolomics Approaches for Glioma Biomarker Identification in a Drosophila melanogaster Model. J Proteome Res 2021; 20:3977-3991. [PMID: 34286978 DOI: 10.1021/acs.jproteome.1c00304] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Human malignant gliomas are the most common type of primary brain tumor. Composed of glial cells and their precursors, they are aggressive and highly invasive, leading to a poor prognosis. Due to the difficulty of surgically removing tumors and their resistance to treatments, novel therapeutic approaches are needed to improve patient life expectancy and comfort. Drosophila melanogaster is a compelling genetic model to better understanding human neurological diseases owing to its high conservation in signaling pathways and cellular content of the brain. Here, glioma has been induced in Drosophila by co-activating the epidermal growth factor receptor and the phosphatidyl-inositol-3 kinase signaling pathways. Complementary nuclear magnetic resonance (NMR) techniques were used to obtain metabolic profiles in the third instar larvae brains. Fresh organs were directly studied by 1H high resolution-magic angle spinning (HR-MAS) NMR, and brain extracts were analyzed by solution-state 1H-NMR. Statistical analyses revealed differential metabolic signatures, impacted metabolic pathways, and glioma biomarkers. Each method was efficient to determine biomarkers. The highlighted metabolites including glucose, myo-inositol, sarcosine, glycine, alanine, and pyruvate for solution-state NMR and proline, myo-inositol, acetate, and glucose for HR-MAS show very good performances in discriminating samples according to their nature with data mining based on receiver operating characteristic curves. Combining results allows for a more complete view of induced disturbances and opens the possibility of deciphering the biochemical mechanisms of these tumors. The identified biomarkers provide a means to rebalance specific pathways through targeted metabolic therapy and to study the effects of pharmacological treatments using Drosophila as a model organism.
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Affiliation(s)
- Marion Maravat
- CNRS, CEMHTI UPR3079, Université d'Orléans, F-45071 Orléans, France
| | | | - Céline Landon
- CNRS, CBM UPR4301, Université d'Orléans, F-45071 Orléans, France
| | - Franck Fayon
- CNRS, CEMHTI UPR3079, Université d'Orléans, F-45071 Orléans, France
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Xu X, Wang L, Zang Q, Li S, Li L, Wang Z, He J, Qiang B, Han W, Zhang R, Peng X, Abliz Z. Rewiring of purine metabolism in response to acidosis stress in glioma stem cells. Cell Death Dis 2021; 12:277. [PMID: 33723244 PMCID: PMC7961141 DOI: 10.1038/s41419-021-03543-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 02/13/2021] [Accepted: 02/19/2021] [Indexed: 01/04/2023]
Abstract
Glioma stem cells (GSCs) contribute to therapy resistance and poor outcomes for glioma patients. A significant feature of GSCs is their ability to grow in an acidic microenvironment. However, the mechanism underlying the rewiring of their metabolism in low pH remains elusive. Here, using metabolomics and metabolic flux approaches, we cultured GSCs at pH 6.8 and pH 7.4 and found that cells cultured in low pH exhibited increased de novo purine nucleotide biosynthesis activity. The overexpression of glucose-6-phosphate dehydrogenase, encoded by G6PD or H6PD, supports the metabolic dependency of GSCs on nucleotides when cultured under acidic conditions, by enhancing the pentose phosphate pathway (PPP). The high level of reduced glutathione (GSH) under acidic conditions also causes demand for the PPP to provide NADPH. Taken together, upregulation of G6PD/H6PD in the PPP plays an important role in acidic-driven purine metabolic reprogramming and confers a predilection toward glioma progression. Our findings indicate that targeting G6PD/H6PD, which are closely related to glioma patient survival, may serve as a promising therapeutic target for improved glioblastoma therapeutics. An integrated metabolomics and metabolic flux analysis, as well as considering microenvironment and cancer stem cells, provide a precise insight into understanding cancer metabolic reprogramming.
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Affiliation(s)
- Xiaoyu Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liping Wang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Biomedical Primate Research Center, Neuroscience Center Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Qingce Zang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shanshan Li
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Biomedical Primate Research Center, Neuroscience Center Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Limei Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhixing Wang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Biomedical Primate Research Center, Neuroscience Center Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Jiuming He
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Boqin Qiang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Biomedical Primate Research Center, Neuroscience Center Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Wei Han
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Biomedical Primate Research Center, Neuroscience Center Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Ruiping Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaozhong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Biomedical Primate Research Center, Neuroscience Center Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China. .,Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.
| | - Zeper Abliz
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. .,Centre for Bioimaging and Systems Biology, Minzu University of China, Beijing, China.
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Gong T, Zhang X, Wei X, Yuan S, Saleh MG, Song Y, Edden RA, Wang G. GSH and GABA decreases in IDH1-mutated low-grade gliomas detected by HERMES spectral editing at 3 T in vivo. Neurochem Int 2020; 141:104889. [PMID: 33115694 PMCID: PMC7704685 DOI: 10.1016/j.neuint.2020.104889] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/18/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022]
Abstract
Isocitrate dehydrogenase 1 (IDH1) mutational status is an important prognostic biomarker in gliomas. γ-aminobutyric acid (GABA) and reduced glutathione (GSH) play an important role in energy production, which is related to tumor progression. Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy (HERMES) is able to detect GABA and GSH in healthy controls. This study aims to examine GABA and GSH alterations in IDH1-mutated low-grade gliomas using HERMES. We prospectively enrolled 14 suspected low-grade gliomas and 6 healthy control patients in this study, all cases underwent a 3 T MRI scan, including T1-weighted imaging and HERMES acquisition with a volume of interest 3 × 3 × 3 cm3. HERMES detects a "GABA+" signal that includes contributions from macromolecules and homocarnosine. GABA+ and GSH in tumor foci (group 1), contralateral cerebral regions (group 2) and healthy controls (group 3) were quantified using Gannet. The fitting errors and SNR of HERMES for GABA+ and GSH were analyzed; FWHM of the unsuppressed water signal was also recorded. The Wilcoxon signed-rank test was performed to test for differences between contralateral GABA+ and GSH levels, and differences in GABA+, GSH and fitting errors/SNR between the three groups were analyzed using analysis of variance (ANOVA). Eleven IDH1-mutant low-grade gliomas (5 Female and 6 Male, age 33-69) and 6 healthy subjects (2 Female and 4 Male, age 35-60) were finally enrolled this study. The mean water linewidth across all subjects was 9.67 ± 2.28 Hz. The Wilcoxon signed-rank test revealed that GABA+ and GSH were decreased significantly in glioma foci compared with contralateral regions, whereas no differences were seen between the left and right regions in healthy controls. ANOVA showed that GABA+ and GSH levels in tumor were lower than contralaterally and in healthy controls, while no differences were observed between the contralateral healthy tissue and healthy controls. No differences of fitting errors or SNR were found between tumors, contralateral regions or healthy controls. Our results suggest that HERMES is a reliable tool to simultaneously measure GABA and GSH alterations in low-grade gliomas with IDH1 mutations.
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Affiliation(s)
- Tao Gong
- Shandong Medical Imaging Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xia Zhang
- Shandong Medical Imaging Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xinhong Wei
- Shandong Medical Imaging Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | | | - Muhammad G Saleh
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Yulu Song
- Shandong Medical Imaging Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Richard A Edden
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Guangbin Wang
- Shandong Medical Imaging Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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33
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The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation. Sci Rep 2020; 10:18742. [PMID: 33128011 PMCID: PMC7603339 DOI: 10.1038/s41598-020-75300-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 10/13/2020] [Indexed: 01/28/2023] Open
Abstract
Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence.
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Communication of Glioma cells with neuronal plasticity: What is the underlying mechanism? Neurochem Int 2020; 141:104879. [PMID: 33068685 DOI: 10.1016/j.neuint.2020.104879] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/26/2020] [Accepted: 10/09/2020] [Indexed: 12/21/2022]
Abstract
There has been a significantly rising discussion on how neuronal plasticity communicates with the glioma growth and invasion. This literature review aims to determine which neurotransmitters, ion channels and signaling pathways are involved in this context, how information is transferred from synaptic sites to the glioma cells and how glioma cells apply established mechanics of synaptic plasticity for their own increment. This work is a compilation of some outstanding findings related to the influence of the glutamate, calcium, potassium, chloride and sodium channels and other important brain plasticity molecules over the glioma progression. These topics also include the relevant molecular signaling data which could prove to be helpful for an effective clinical management of brain tumors in the future.
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35
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Fumagalli A, Heuninck J, Pizzoccaro A, Moutin E, Koenen J, Séveno M, Durroux T, Junier MP, Schlecht-Louf G, Bachelerie F, Schütz D, Stumm R, Smit MJ, Guérineau NC, Chaumont-Dubel S, Marin P. The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication. Nat Commun 2020; 11:4855. [PMID: 32978390 PMCID: PMC7519114 DOI: 10.1038/s41467-020-18634-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 09/02/2020] [Indexed: 12/12/2022] Open
Abstract
The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in tumors promotes cell proliferation and invasiveness. The intracellular signaling pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by identifying the interactome of ACKR3. Here, we report that recombinant ACKR3 expressed in HEK293T cells recruits the gap junction protein Connexin 43 (Cx43). Cx43 and ACKR3 are co-expressed in mouse brain astrocytes and human glioblastoma cells and form a complex in embryonic mouse brain. Functional in vitro studies show enhanced ACKR3 interaction with Cx43 upon ACKR3 agonist stimulation. Furthermore, ACKR3 activation promotes β-arrestin2- and dynamin-dependent Cx43 internalization to inhibit gap junctional intercellular communication in primary astrocytes. These results demonstrate a functional link between ACKR3 and gap junctions that might be of pathophysiological relevance. The atypical chemokine receptor 3 (ACKR3) is known to regulate cell migration, but the underlying mechanisms are unclear. Here, the authors show, from an interactome analysis, ACKR3 association with the gap junction protein Connexin 43 in vivo and ACKR3-mediated inhibition of astrocyte gap junctional communication.
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Affiliation(s)
- Amos Fumagalli
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Joyce Heuninck
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Anne Pizzoccaro
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Enora Moutin
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Joyce Koenen
- Université Paris-Saclay, Inserm, Inflammation, Microbiome and Immunosurveillance, 92140, Clamart, France.,Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081, HV, Amsterdam, The Netherlands
| | - Martial Séveno
- Biocampus Montpellier, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Thierry Durroux
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Marie-Pierre Junier
- CNRS UMR8246, Inserm U1130, Neuroscience Paris Seine-IBPS, Sorbonne Universités, Paris, France
| | - Géraldine Schlecht-Louf
- Université Paris-Saclay, Inserm, Inflammation, Microbiome and Immunosurveillance, 92140, Clamart, France
| | - Francoise Bachelerie
- Université Paris-Saclay, Inserm, Inflammation, Microbiome and Immunosurveillance, 92140, Clamart, France
| | - Dagmar Schütz
- Institute of Pharmacology and Toxicology, Jena University Hospital, 07747, Jena, Germany
| | - Ralf Stumm
- Institute of Pharmacology and Toxicology, Jena University Hospital, 07747, Jena, Germany
| | - Martine J Smit
- Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081, HV, Amsterdam, The Netherlands
| | - Nathalie C Guérineau
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Séverine Chaumont-Dubel
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Philippe Marin
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.
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36
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Deng XY, Gan XX, Feng JH, Cai WS, Wang XQ, Shen L, Luo HT, Chen Z, Guo M, Cao J, Shen F, Xu B. ALDH5A1 acts as a tumour promoter and has a prognostic impact in papillary thyroid carcinoma. Cell Biochem Funct 2020; 39:317-325. [PMID: 32881051 DOI: 10.1002/cbf.3584] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/12/2020] [Accepted: 08/01/2020] [Indexed: 12/13/2022]
Abstract
Thyroid cancer is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for 80%-90% of thyroid cancers. Accumulating studies reported that mitochondria plays an important role in the regulation of cell proliferation. ALDH5A1, may function as an oncogene or tumour suppressor in various human cancers, and the role of ALDH5A1 in PTC is still unclear. The aim of this study was to investigate the clinical significance of ALDH5A1 expression and its functions in PTC. In this present study, we studied ALDH5A1 expression on primary papillary thyroid carcinoma (PTC) in The Cancer Genome Atlas (TCGA) database. Results showed that the levels of ALDH5A1 were found positively correlated with tumour stage, metastasis, lymph node stage, and higher levels of ALDH5A1 demonstrated poor disease-free survival (DFS). Immunohistochemistry (IHC) revealed that significantly higher expression of ALDH5A1 was found in PTC tissues. On the other hand, knockdown of ALDH5A1 significantly inhibited PTC cell proliferation, migration and invasion detection found the migration and invasion of cells also were hindered when ALDH5A1 level was reduced. The knockdown of ALDH5A1 inhibited the expression of Vimentin and promoted the expression of E-cadherin. In brief, knockdown of ALDH5A1may act as a novel molecular target for the prevention and treatment of PTC. SIGNIFICANCE OF THE STUDY: The present study focused on the role and the potential mechanism of ALDH5A1 in papillary thyroid carcinoma. We demonstrated that reduced expression of ALDH5A1 might inhibit the progression of TC by inhibiting cell proliferation, migration and invasion and reversing epithelial-mesenchymal transition (EMT). The findings ensured the interaction relation between ALDH5A1 and EMT in PTC, providing a novel biological marker for PTC and enriching the potential strategies for TC treatment.
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Affiliation(s)
- Xing-Yan Deng
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Xiao-Xiong Gan
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Jian-Hua Feng
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Wen-Song Cai
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Xin-Quan Wang
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China
| | - Liang Shen
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Hong-Tu Luo
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Zhen Chen
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Mengli Guo
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Jie Cao
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Fei Shen
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
| | - Bo Xu
- Department of Thyroid Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China.,Department of Thyroid Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, PR China
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37
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Andersen JV, Jakobsen E, Westi EW, Lie MEK, Voss CM, Aldana BI, Schousboe A, Wellendorph P, Bak LK, Pinborg LH, Waagepetersen HS. Extensive astrocyte metabolism of γ-aminobutyric acid (GABA) sustains glutamine synthesis in the mammalian cerebral cortex. Glia 2020; 68:2601-2612. [PMID: 32584476 DOI: 10.1002/glia.23872] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/15/2022]
Abstract
Synaptic transmission is closely linked to brain energy and neurotransmitter metabolism. However, the extent of brain metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and the relative metabolic contributions of neurons and astrocytes, are yet unknown. The present study was designed to investigate the functional significance of brain GABA metabolism using isolated mouse cerebral cortical slices and slices of neurosurgically resected neocortical human tissue of the temporal lobe. By using dynamic isotope labeling, with [15 N]GABA and [U-13 C]GABA as metabolic substrates, we show that both mouse and human brain slices exhibit a large capacity for GABA metabolism. Both the nitrogen and the carbon backbone of GABA strongly support glutamine synthesis, particularly in the human cerebral cortex, indicative of active astrocytic GABA metabolism. This was further substantiated by pharmacological inhibition of the primary astrocytic GABA transporter subtype 3 (GAT3), by (S)-SNAP-5114 or 1-benzyl-5-chloro-2,3-dihydro-1H-indole-2,3-dione (compound 34), leading to significant reductions in oxidative GABA carbon metabolism. Interestingly, this was not the case when tiagabine was used to specifically inhibit GAT1, which is predominantly found on neurons. Finally, we show that acute GABA exposure does not directly stimulate glycolytic activity nor oxidative metabolism in cultured astrocytes, but can be used as an additional substrate to enhance uncoupled respiration. These results clearly show that GABA is actively metabolized in astrocytes, particularly for the synthesis of glutamine, and challenge the current view that synaptic GABA homeostasis is maintained primarily by presynaptic recycling.
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Affiliation(s)
- Jens V Andersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emil Jakobsen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emil W Westi
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Maria E K Lie
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline M Voss
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Blanca I Aldana
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Arne Schousboe
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Petrine Wellendorph
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lasse K Bak
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars H Pinborg
- Epilepsy Clinic and Neurobiology Research Unit, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Helle S Waagepetersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Identification of potential crucial genes and molecular mechanisms in glioblastoma multiforme by bioinformatics analysis. Mol Med Rep 2020; 22:859-869. [PMID: 32467990 PMCID: PMC7339479 DOI: 10.3892/mmr.2020.11160] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 04/04/2020] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and malignant brain tumor of the adult central nervous system and is associated with poor prognosis. The present study aimed to identify the hub genes in GBM in order to improve the current understanding of the underlying mechanism of GBM. The RNA-seq data were downloaded from The Cancer Genome Atlas database. The edgeR package in R software was used to identify differentially expressed genes (DEGs) between two groups: Glioblastoma samples and normal brain samples. Gene Ontology (GO) functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed using Database for Annotation, Visualization and Integrated Discovery software. Additionally, Cytoscape and Search Tool for the Retrieval of Interacting Genes/Proteins tools were used for the protein-protein interaction network, while the highly connected modules were extracted from this network using the Minimal Common Oncology Data Elements plugin. Next, the prognostic significance of the candidate hub genes was analyzed using UALCAN. In addition, the identified hub genes were verified by reverse transcription-quantitative (RT-q) PCR. In total, 1,483 DEGs were identified between GBM and control samples, including 954 upregulated genes and 529 downregulated genes (P<0.01; fold-change >16) and these genes were involved in different GO terms and signaling pathways. Furthermore, CDK1, BUB1, BUB1B, CENPA and GNG3 were identified as key genes in the GBM samples. The UALCAN tool verified that higher expression level of CENPA was relevant to poorer overall survival rates. In conclusion, CDK1, BUB1, BUB1B, CENPA and GNG3 were found to be potential biomarkers for GBM. Additionally, ‘cell cycle’ and ‘γ-aminobutyric acid signaling’ pathways may serve a significant role in the pathogenesis of GBM.
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39
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Rodrigues L, Cravo P, Viveiros M. Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs. Expert Rev Anti Infect Ther 2020; 18:741-757. [PMID: 32434397 DOI: 10.1080/14787210.2020.1760845] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In 2018, an estimated 377,000 people developed multidrug-resistant tuberculosis (MDR-TB), urging for new effective treatments. In the last years, it has been accepted that efflux pumps play an important role in the evolution of drug resistance. Strategies are required to mitigate the consequences of the activity of efflux pumps. AREAS COVERED Based upon the literature available in PubMed, up to February 2020, on the diversity of efflux pumps in Mycobacterium tuberculosis and their association with drug resistance, studies that identified efflux inhibitors and their effect on restoring the activity of antimicrobials subjected to efflux are reviewed. These support a new strategy for the development of anti-TB drugs, including efflux inhibitors, using in silico drug repurposing. EXPERT OPINION The current literature highlights the contribution of efflux pumps in drug resistance in M. tuberculosis and that efflux inhibitors may help to ensure the effectiveness of anti-TB drugs. However, despite the usefulness of efflux inhibitors in in vitro studies, in most cases their application in vivo is restricted due to toxicity. In a time when new drugs are needed to fight MDR-TB and extensively drug-resistant TB, cost-effective strategies to identify safer efflux inhibitors should be implemented in drug discovery programs.
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Affiliation(s)
- Liliana Rodrigues
- Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL , Lisboa, Portugal
| | - Pedro Cravo
- Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL , Lisboa, Portugal
| | - Miguel Viveiros
- Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL , Lisboa, Portugal
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40
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Nicolini A, Rossi G, Ferrari P, Carpi A. Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity. Semin Cancer Biol 2020; 79:68-82. [PMID: 32201368 DOI: 10.1016/j.semcancer.2020.03.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/20/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023]
Abstract
In the last decade, a large amount of research has focused on elucidating the mechanisms that account for homing disseminated cancer cells (DCCs) from solid tumours to distant organs, which successively progress to overt metastatic disease; this is currently incurable. A better understanding of DCC behaviour is expected to allow detectable metastasis prevention by more effectively targeting 'metastatic seeds before they sprout'. As DCC biology co-evolved with that of the primary tumour, and due to the many similarities between them, the term 'niche' has been borrowed from normal adult stem cells (ASCs) to define the site of DCC metastatic colonisation. Moreover, heterogeneity, survival, protection, stemness and plasticity as well as the prolonged G0-G1 dormant state in the metastatic niche have been the main aspects of intense investigation. Consistent with these findings, in solid cancers with minimal residual disease (MRD), it has been proposed to prolong adjuvant therapy by targeting specific molecular pathway(s) involving DCC dormancy. However, so far, few disappointing clinical data have been reported. As an alternative strategy, because immune-surveillance contributes to the steady state of the DCC population and likely to the G0-G1 state of cancer cells, we have used prolonged immune-modulatory cytostatic chemotherapy, active immune stimulation with an INF-β/IL-2 sequence or drugs inhibiting myeloid-derived suppressor cell (MDSC)/Treg-mediated immune suppression. This strategy, mainly aimed at boosting the immune response, is based on recent findings suggesting the downregulation of immune escape mechanisms as well as other principal hallmarks during the G0-G1 state and/or in MRD. Preliminary clinical and/or laboratory data suggest the efficacy of this strategy in gastrointestinal and some endocrine-dependent cancers. Following this, we propose therapeutic schedules to prevent DCC activation and proliferation in solid cancers at a high risk of relapse or as maintenance therapy in metastatic patients after complete response (CR) to conventional treatment.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Italy.
| | - Giuseppe Rossi
- National Research Council (CNR), Epidemiology and Biostatistics Unit, Institute of Clinical Physiology and G. Monasterio Foundation, Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology 1, University Hospital of Pisa, Pisa, Italy
| | - Angelo Carpi
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
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41
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Metabolic regulation of Ganoderma lucidum extracts in high sugar and fat diet-induced obese mice by regulating the gut-brain axis. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103639] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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42
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Saurty-Seerunghen MS, Bellenger L, El-Habr EA, Delaunay V, Garnier D, Chneiweiss H, Antoniewski C, Morvan-Dubois G, Junier MP. Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells. Acta Neuropathol Commun 2019; 7:155. [PMID: 31619292 PMCID: PMC6796454 DOI: 10.1186/s40478-019-0819-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 09/29/2019] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients’ diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using independent datasets of glioblastoma cell and tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.
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Zeniou M, Nguekeu-Zebaze L, Dantzer F. Therapeutic considerations of PARP in stem cell biology: Relevance in cancer and beyond. Biochem Pharmacol 2019; 167:107-115. [PMID: 31202733 DOI: 10.1016/j.bcp.2019.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/11/2019] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are of fundamental importance in tumor progression because of their tumor-initiating properties, their resistance to radio- and chemotherapy, their invasive properties and their propensity to escape immune responses that together contribute to tumor relapse. These highly aggressive features underscore the importance of constantly identifying new and innovative therapeutic solutions to eradicate these cells. In this narrative review we discuss recent findings on the involvement of PARP family members in cancer stem cell biology and the benefit of their inhibition. Nonetheless, an important limitation in the use of PARP inhibitors is the emergence of a prominent function of PARP1 in non-cancer stem cell biology including stem cell maintenance and differentiation during development, neurogenesis or adipogenesis. Thus, we also summarize the dominant discoveries revealing the importance of PARP1 in normal stem cell biology.
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Affiliation(s)
- M Zeniou
- Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France
| | - L Nguekeu-Zebaze
- Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France
| | - F Dantzer
- Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France.
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Hujber Z, Horváth G, Petővári G, Krencz I, Dankó T, Mészáros K, Rajnai H, Szoboszlai N, Leenders WPJ, Jeney A, Tretter L, Sebestyén A. GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:271. [PMID: 30404651 PMCID: PMC6223071 DOI: 10.1186/s13046-018-0946-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 10/26/2018] [Indexed: 12/18/2022]
Abstract
Background Bioenergetic characterisation of malignant tissues revealed that different tumour cells can catabolise multiple substrates as salvage pathways, in response to metabolic stress. Altered metabolism in gliomas has received a lot of attention, especially in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate (2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas, collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal functions. Methods Metabolic characteristics of human glioma cell models – including mitochondrial function, glycolytic pathway and energy substrate oxidation – in relation to IDH mutation status and after 2-HG incubation were studied to understand the Janus-faced role of IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry. Results U251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA in SSADH expressing cells. SSADH protein overexpression was found in almost all studied human cases with no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation). Conclusions Our findings demonstrate that SSADH expression may participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA oxidation capacity may contribute to proliferation and worse prognosis of gliomas. Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells. Based on these data, GABA oxidation and SSADH activity could be additional therapeutic targets in gliomas/glioblastomas. Electronic supplementary material The online version of this article (10.1186/s13046-018-0946-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zoltán Hujber
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Gergő Horváth
- Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, Budapest, 1444, Hungary
| | - Gábor Petővári
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Ildikó Krencz
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Titanilla Dankó
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Katalin Mészáros
- Hungarian Academy of Sciences - Momentum Hereditary Endocrine Tumours Research Group, Semmelweis University - National Bionics Program, Budapest, 1088, Hungary
| | - Hajnalka Rajnai
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Norbert Szoboszlai
- Laboratory of Environmental Chemistry and Bioanalytics, Department of Analytical Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, 1518, Hungary
| | - William P J Leenders
- Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands
| | - András Jeney
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - László Tretter
- Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, Budapest, 1444, Hungary
| | - Anna Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary.
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Deng Y, Luo S, Zhang X, Zou C, Yuan H, Liao G, Xu L, Deng C, Lan Y, Zhao T, Gao X, Xiao Y, Li X. A pan-cancer atlas of cancer hallmark-associated candidate driver lncRNAs. Mol Oncol 2018; 12:1980-2005. [PMID: 30216655 PMCID: PMC6210054 DOI: 10.1002/1878-0261.12381] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 07/21/2018] [Accepted: 09/03/2018] [Indexed: 12/12/2022] Open
Abstract
Substantial cancer genome sequencing efforts have discovered many important driver genes contributing to tumorigenesis. However, very little is known about the genetic alterations of long non‐coding RNAs (lncRNAs) in cancer. Thus, there is a need for systematic surveys of driver lncRNAs. Through integrative analysis of 5918 tumors across 11 cancer types, we revealed that lncRNAs have undergone dramatic genomic alterations, many of which are mutually exclusive with well‐known cancer genes. Using the hypothesis of functional redundancy of mutual exclusivity, we developed a computational framework to identify driver lncRNAs associated with different cancer hallmarks. Applying it to pan‐cancer data, we identified 378 candidate driver lncRNAs whose genomic features highly resemble the known cancer driver genes (e.g. high conservation and early replication). We further validated the candidate driver lncRNAs involved in ‘Tissue Invasion and Metastasis’ in lung adenocarcinoma and breast cancer, and also highlighted their potential roles in improving clinical outcomes. In summary, we have generated a comprehensive landscape of cancer candidate driver lncRNAs that could act as a starting point for future functional explorations, as well as the identification of biomarkers and lncRNA‐based target therapy.
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Affiliation(s)
- Yulan Deng
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Shangyi Luo
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Xinxin Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Chaoxia Zou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, China
| | - Huating Yuan
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Gaoming Liao
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Liwen Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Chunyu Deng
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Yujia Lan
- College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Tingting Zhao
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, China
| | - Yun Xiao
- College of Bioinformatics Science and Technology, Harbin Medical University, China.,Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, China
| | - Xia Li
- College of Bioinformatics Science and Technology, Harbin Medical University, China.,Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, China
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46
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Broekman ML, Maas SLN, Abels ER, Mempel TR, Krichevsky AM, Breakefield XO. Multidimensional communication in the microenvirons of glioblastoma. Nat Rev Neurol 2018; 14:482-495. [PMID: 29985475 PMCID: PMC6425928 DOI: 10.1038/s41582-018-0025-8] [Citation(s) in RCA: 403] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth. Tumour cells also suppress adaptive immune responses, and our increasing understanding of how T cells access the brain and how the tumour thwarts the immune response offers new strategies for mobilizing an antitumour response. Tumours also subvert normal brain cells - including endothelial cells, neurons and astrocytes - to create a microenviron that favours tumour success. Overall, after glioblastoma-induced phenotypic modifications, normal cells cooperate with tumour cells to promote tumour proliferation, invasion of the brain, immune suppression and angiogenesis. This glioblastoma takeover of the brain involves multiple modes of communication, including soluble factors such as chemokines and cytokines, direct cell-cell contact, extracellular vesicles (including exosomes and microvesicles) and connecting nanotubes and microtubes. Understanding these multidimensional communications between the tumour and the cells in its environs could open new avenues for therapy.
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Affiliation(s)
- Marike L Broekman
- Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
- Department of Neurosurgery, Brain Center Rudolf Magnus, Institute of Neurosciences, University Medical Center, Heidelberglaan, Utrecht, Netherlands.
| | - Sybren L N Maas
- Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Brain Center Rudolf Magnus, Institute of Neurosciences, University Medical Center, Heidelberglaan, Utrecht, Netherlands
| | - Erik R Abels
- Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
| | - Thorsten R Mempel
- The Center for Immunology and Inflammatory Diseases and Department of Medicine, Massachusetts General Hospital, Charlestown, MA, USA
- Program in Immunology, Harvard Medical School, Boston, MA, USA
| | - Anna M Krichevsky
- Department of Neurology, Ann Romney Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Xandra O Breakefield
- Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
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Vasilogiannakopoulou T, Piperi C, Papavassiliou AG. Impact of Aldehyde Dehydrogenase Activity on Gliomas. Trends Pharmacol Sci 2018; 39:605-609. [PMID: 29728268 DOI: 10.1016/j.tips.2018.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/04/2018] [Accepted: 04/04/2018] [Indexed: 12/18/2022]
Abstract
High-grade gliomas are primary brain tumors with a highly aggressive, invasive phenotype and dismal outcome. Targeting cell metabolism and cancer bioenergetics has emerged as a potential effective therapeutic approach. Selective aldehyde dehydrogenase isoenzyme activity regulates glioma tumor growth, invasiveness, and resistance to current treatments, and has potential as a therapeutic target.
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Affiliation(s)
- Theodora Vasilogiannakopoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; These authors contributed equally to this work
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; These authors contributed equally to this work
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
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Han W, Hu P, Wu F, Wang S, Hu Y, Li S, Jiang T, Qiang B, Peng X. FHL3 links cell growth and self-renewal by modulating SOX4 in glioma. Cell Death Differ 2018; 26:796-811. [PMID: 29955125 DOI: 10.1038/s41418-018-0152-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 05/13/2018] [Accepted: 06/05/2018] [Indexed: 12/21/2022] Open
Abstract
Differentiation status significantly affects the properties of malignant glioma cells, with non-stem cells inducing tumor enlargement and stem-like cells driving tumor initiation and treatment resistance. It is not completely understood how the same protein can have a distinct role in these cell populations. Here, we report that four and a half LIM domain protein 3 (FHL3) has an inhibitory effect on proliferation in non-stem glioma cells and a non-proliferative effect in glioma stem cells (GSCs). In GSCs, we show that FHL3 interacts with the Smad2/3 protein complex at the SOX4 promoter region, inhibits SOX4 transcriptional activity by recruiting PPM1A phosphatase to Smad2/3, and then suppresses GSC tumor sphere formation and self-renewal in vitro and in vivo via downregulation of SOX2 expression. Altogether, these findings highlight the role of FHL3 as a stemness-suppressor in regulation of the Smad2/3-SOX4-SOX2 axis in glioma.
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Affiliation(s)
- Wei Han
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Peishan Hu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Fan Wu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, 100050, Beijing, China
| | - Shanshan Wang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Yan Hu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Shanshan Li
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Tao Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, 100050, Beijing, China
| | - Boqin Qiang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China.
| | - Xiaozhong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China. .,Institute of Medical Biology, Chinese Academy of Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, 650118, Kunming, China.
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Chen W, Zebaze LN, Dong J, Chézeau L, Inquimbert P, Hugel S, Niu S, Bihel F, Boutant E, Réal E, Villa P, Junier MP, Chneiweiss H, Hibert M, Haiech J, Kilhoffer MC, Zeniou M. WNK1 kinase and its partners Akt, SGK1 and NBC-family Na +/HCO3 - cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling. Oncotarget 2018; 9:27197-27219. [PMID: 29930759 PMCID: PMC6007472 DOI: 10.18632/oncotarget.25509] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 05/10/2018] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma is a highly heterogeneous brain tumor. The presence of cancer cells with stem-like and tumor initiation/propagation properties contributes to poor prognosis. Glioblastoma cancer stem-like cells (GSC) reside in hypoxic and acidic niches favoring cell quiescence and drug resistance. A high throughput screening recently identified the laxative Bisacodyl as a cytotoxic compound targeting quiescent GSC placed in acidic microenvironments. Bisacodyl activity requires its hydrolysis into DDPM, its pharmacologically active derivative. Bisacodyl was further shown to induce tumor shrinking and increase survival in in vivo glioblastoma models. Here we explored the cellular mechanism underlying Bisacodyl cytotoxic effects using quiescent GSC in an acidic microenvironment and GSC-derived 3D macro-spheres. These spheres mimic many aspects of glioblastoma tumors in vivo, including hypoxic/acidic areas containing quiescent cells. Phosphokinase protein arrays combined with pharmacological and genetic modulation of signaling pathways point to the WNK1 serine/threonine protein kinase as a mediator of Bisacodyl cytotoxic effect in both cell models. WNK1 partners including the Akt and SGK1 protein kinases and NBC-family Na+/HCO3− cotransporters were shown to participate in the compound’s effect on GSC. Overall, our findings uncover novel potential therapeutic targets for combatting glioblastoma which is presently an incurable disease.
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Affiliation(s)
- Wanyin Chen
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Leonel Nguekeu Zebaze
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Jihu Dong
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Laëtitia Chézeau
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Perrine Inquimbert
- Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 67084 Strasbourg, France; Université de Strasbourg, Strasbourg 67084, France
| | - Sylvain Hugel
- Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 67084 Strasbourg, France; Université de Strasbourg, Strasbourg 67084, France
| | - Songlin Niu
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Fréderic Bihel
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Emmanuel Boutant
- Laboratoire de Bioimagerie et Pathologies - LBP, UMR7021, Centre National de la Recherche Scientifique/Université de Strasbourg, Faculté de Pharmacie, Illkirch 67401, France
| | - Eléonore Réal
- Laboratoire de Bioimagerie et Pathologies - LBP, UMR7021, Centre National de la Recherche Scientifique/Université de Strasbourg, Faculté de Pharmacie, Illkirch 67401, France
| | - Pascal Villa
- Plateforme de Chimie Biologie Intégrative (PCBIS), Université de Strasbourg/CNRS UMS 3286, Laboratoire d'Excellence Medalis, ESBS Pôle API-Bld Sébastien Brant, Illkirch 67401, France
| | - Marie-Pierre Junier
- Neuroscience Paris Seine-IBPS, CNRS UMR 8246/Inserm U1130/UPMC UMCR18, Paris 75005, France
| | - Hervé Chneiweiss
- Neuroscience Paris Seine-IBPS, CNRS UMR 8246/Inserm U1130/UPMC UMCR18, Paris 75005, France
| | - Marcel Hibert
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Jacques Haiech
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Marie-Claude Kilhoffer
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
| | - Maria Zeniou
- Laboratoire d'Innovation Thérapeutique, Centre National de la Recherche Scientifique/Université de Strasbourg, UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Illkirch 67401, France
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Glowacka WK, Jain H, Okura M, Maimaitiming A, Mamatjan Y, Nejad R, Farooq H, Taylor MD, Aldape K, Kongkham P. 5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma. Acta Neuropathol 2018; 135:617-634. [PMID: 29428975 PMCID: PMC5978937 DOI: 10.1007/s00401-018-1821-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 01/18/2018] [Accepted: 02/07/2018] [Indexed: 01/12/2023]
Abstract
Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.
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