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Harland AJ, Perks CM. IGFBP-2 and IGF-II: Key Components of the Neural Stem Cell Niche? Implications for Glioblastoma Pathogenesis. Int J Mol Sci 2025; 26:4749. [PMID: 40429889 PMCID: PMC12111820 DOI: 10.3390/ijms26104749] [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: 04/02/2025] [Revised: 05/09/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Glioblastoma is a fatal and aggressive cancer with no cure. It is becoming increasingly clear that glioblastoma initiation is a result of adult neural stem cell (NSC) transformation-most likely those within the subventricular zone (SVZ). Indeed, transcriptomic analysis indicates that glioblastomas are reminiscent of a neurodevelopmental hierarchy, in which neural stem and progenitor markers are widely expressed by tumour stem-like cells. However, NSC fates and the cues that drive them are poorly understood. Studying the crosstalk within NSC niches may better inform our understanding of glioblastoma initiation and development. Insulin-like growth factor binding protein 2 (IGFBP-2) has a well-established prognostic role in glioblastoma, and cell-based mechanistic studies show the independent activation of downstream oncogenic pathways. However, IGFBP-2 is more commonly recognised as a modulator of insulin-like growth factors (IGFs) for receptor tyrosine kinase signal propagation or attenuation. In the adult human brain, both IGFBP-2 and IGF-II expression are retained in the choroid plexus (ChP) and secreted into the cerebral spinal fluid (CSF). Moreover, secretion by closely associated cells and NSCs themselves position IGFBP-2 and IGF-II as interesting factors within the NSC niche. In this review, we will highlight the experimental findings that show IGFBP-2 and IGF-II influence NSC behaviour. Moreover, we will link this to glioblastoma biology and demonstrate the requirement for further analysis of these factors in glioma stem cells (GSCs).
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Affiliation(s)
| | - Claire M. Perks
- Cancer Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK;
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Tian Y, Wang Z, Sun M, Li J, Zheng W, Yang F, Zhang Z. Olig1/2 Drive Astrocytic Glioblastoma Proliferation Through Transcriptional Co-Regulation of Various Cyclins. Genes (Basel) 2025; 16:573. [PMID: 40428395 PMCID: PMC12111234 DOI: 10.3390/genes16050573] [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: 04/13/2025] [Revised: 05/06/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
As the most aggressive primary brain tumor, glioblastoma (GBM) is considered incurable due to its molecular heterogeneity and therapy resistance. Identifying key regulatory factors in GBM is critical for developing effective therapeutic strategies. Based on the analysis of TCGA data, we confirmed a robust co-expression and correlation of OLIG1 and OLIG2 in human GBM. However, their roles in the astrocytic GBM subtype remain unclear. In this study, we first establish an astrocytic-featured GBM mouse model by introducing PiggyBac-driven hEGFRvIII plasmids and demonstrate that both OLIG1 and OLIG2 are highly expressed within this context. Next, using CRISPR/Cas9 technology to knockout Olig1/2, we found that astrocyte differentiation markers such as GFAP, SOX9, and HOPX were preserved, but tumor cell proliferation was significantly diminished. Mechanistically, CUT&Tag-seq revealed that OLIG1/2 directly binds to the promoter region of various cyclins (Cdk4, Ccne2, Ccnd3, and Ccnd1), where an enrichment of the active histone marker H3K4me3 was observed, indicating transcriptional activation of the genes. Notably, Olig1/2 knockout did not suppress tumor initiation or migration, suggesting that their primary role is to amplify proliferation rather than to drive tumorigenesis. This study defines Olig1 and Olig2 as master regulators of GBM proliferation through various cyclins, thereby offering a novel therapeutic target.
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Affiliation(s)
- Yu Tian
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Fudan University, Shanghai 200032, China; (Y.T.); (Z.W.); (M.S.); (J.L.); (W.Z.)
| | - Ziwu Wang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Fudan University, Shanghai 200032, China; (Y.T.); (Z.W.); (M.S.); (J.L.); (W.Z.)
| | - Mengge Sun
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Fudan University, Shanghai 200032, China; (Y.T.); (Z.W.); (M.S.); (J.L.); (W.Z.)
| | - Jialin Li
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Fudan University, Shanghai 200032, China; (Y.T.); (Z.W.); (M.S.); (J.L.); (W.Z.)
| | - Wenhui Zheng
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Fudan University, Shanghai 200032, China; (Y.T.); (Z.W.); (M.S.); (J.L.); (W.Z.)
| | - Feihong Yang
- Department of Anesthesiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
| | - Zhuangzhi Zhang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Fudan University, Shanghai 200032, China; (Y.T.); (Z.W.); (M.S.); (J.L.); (W.Z.)
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3
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Li PC, Yun DB, Huang YX, Huang QY. Prognostic significance of oligodendrocyte transcription factor 2 expression in glioma patients: A systematic review and meta-analysis. World J Clin Cases 2024; 12:5739-5748. [PMID: 39247740 PMCID: PMC11263059 DOI: 10.12998/wjcc.v12.i25.5739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/27/2024] [Accepted: 06/24/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Gliomas are the most common primary central nervous system neoplasm. Despite recent advances in the diagnosis and treatment of gliomas, patient prognosis remains dismal. Therefore, it is imperative to identify novel diagnostic biomarkers and therapeutic targets of glioma to effectively improve treatment outcomes. AIM To investigate the association between oligodendrocyte transcription factor 2 (Olig2) expression and the outcomes of glioma patients. METHODS The PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were searched for studies (published up to October 2023) that investigated the relationship between Olig2 expression and prognosis of glioma patients. The quality of the studies was assessed using the Newcastle Ottawa Scale. Data analyses were performed using Stata Version 12.0 software. RESULTS A total of 1205 glioma patients from six studies were included in the meta-analysis. High Olig2 expression was associated with better outcomes in glioma patients [hazard ratio (HR): 0.81; 95% (confidence interval) CI: 0.51-1.27; P = 0.000]. Furthermore, the results of subgroup meta-analysis showed that high expression of Olig2 was associated with poor overall survival in European patients (HR: 1.34; 95%CI: 0.79-2.27) and better prognosis in Asian patients (HR: 0.43; 95%CI: 0.22-0.84). The sensitivity analysis showed that no single study had a significant effect on pooled HR, and there was also no indication of publication bias according to the Egger's and Begger's P value test or funnel plot test. CONCLUSION High Olig2 expression may have a positive impact on the prognosis of glioma patients, and should be investigated further as a prognostic biomarker and therapeutic target for glioma.
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Affiliation(s)
- Peng-Cheng Li
- Department of Neurosurgery, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - De-Bo Yun
- Department of Neurosurgery, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Ya-Xin Huang
- Department of Transfusion, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Qian-Yi Huang
- Department of Transfusion, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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4
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Liu X, Wu L, Wang L, Li Y. Identification and classification of glioma subtypes based on RNA-binding proteins. Comput Biol Med 2024; 174:108404. [PMID: 38582000 DOI: 10.1016/j.compbiomed.2024.108404] [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: 12/04/2023] [Revised: 03/23/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND Glioma is a common and aggressive primary malignant cancer known for its high morbidity, mortality, and recurrence rates. Despite this, treatment options for glioma are currently restricted. The dysregulation of RBPs has been linked to the advancement of several types of cancer, but their precise role in glioma evolution is still not fully understood. This study sought to investigate how RBPs may impact the development and prognosis of glioma, with potential implications for prognosis and therapy. METHODS RNA-seq profiles of glioma and corresponding clinical data from the CGGA database were initially collected for analysis. Unsupervised clustering was utilized to identify crucial tumor subtypes in glioma development. Subsequent time-series analysis and MS model were employed to track the progression of these identified subtypes. RBPs playing a significant role in glioma progression were then pinpointed using WGCNA and Lasso Cox regression models. Functional analysis of these key RBP-related genes was conducted through GSEA. Additionally, the CIBERSORT algorithm was utilized to estimate immune infiltrating cells, while the STRING database was consulted to uncover potential mechanisms of the identified biomarkers. RESULTS Six tumor subgroups were identified and found to be highly homogeneous within each subgroup. The progression stages of these tumor subgroups were determined using time-series analysis and a MS model. Through WGCNA, Lasso Cox, and multivariate Cox regression analysis, it was confirmed that BCLAF1 is correlated with survival in glioma patients and is closely linked to glioma progression. Functional annotation suggests that BCLAF1 may impact glioma progression by influencing RNA splicing, which in turn affects the cell cycle, Wnt signaling pathway, and other cancer development pathways. CONCLUSIONS The study initially identified six subtypes of glioma progression and assessed their malignancy ranking. Furthermore, it was determined that BCLAF1 could serve as an RBP-related prognostic marker, offering significant implications for the clinical diagnosis and personalized treatment of glioma.
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Affiliation(s)
- Xudong Liu
- School of Medicine, Chongqing University, Chongqing, 400044, China; Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Lei Wu
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Lei Wang
- College of Life Sciences, Xinyang Normal University, Xinyang, 464000, China.
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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Kim HJ, Jeon HM, Batara DC, Lee S, Lee SJ, Yin J, Park SI, Park M, Seo JB, Hwang J, Oh YJ, Suh SS, Kim SH. CREB5 promotes the proliferation and self-renewal ability of glioma stem cells. Cell Death Discov 2024; 10:103. [PMID: 38418476 PMCID: PMC10901809 DOI: 10.1038/s41420-024-01873-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 02/07/2024] [Accepted: 02/15/2024] [Indexed: 03/01/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most fatal form of brain cancer in humans, with a dismal prognosis and a median overall survival rate of less than 15 months upon diagnosis. Glioma stem cells (GSCs), have recently been identified as key contributors in both tumor initiation and therapeutic resistance in GBM. Both public dataset analysis and direct differentiation experiments on GSCs have demonstrated that CREB5 is more highly expressed in undifferentiated GSCs than in differentiated GSCs. Additionally, gene silencing by short hairpin RNA (shRNA) of CREB5 has prevented the proliferation and self-renewal ability of GSCs in vitro and decreased their tumor forming ability in vivo. Meanwhile, RNA-sequencing, luciferase reporter assay, and ChIP assay have all demonstrated the closely association between CREB5 and OLIG2. These findings suggest that targeting CREB5 could be an effective approach to overcoming GSCs.
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Affiliation(s)
- Hyun-Jin Kim
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Hye-Min Jeon
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Don Carlo Batara
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Seongsoo Lee
- Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju, 61186, Republic of Korea
| | - Suk Jun Lee
- Department of Biomedical Laboratory Science, College of Health & Medical Sciences, Cheongju University, Chungbuk, 360764, Republic of Korea
| | - Jinlong Yin
- Henan-Macquarie Uni Joint Centre for Biomedical Innovation, Academy for Advanced Interdisciplinary Studies, Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Sang-Ik Park
- Laboratory of Veterinary Pathology, BK21 FOUR Program, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Minha Park
- Department of Biomedicine, BK21 FOUR Program, Health & Life Convergence Sciences, Biomedical and Healthcare Research Institute, Mokpo National University, Muan, 58554, Republic of Korea
| | - Jong Bae Seo
- Department of Biomedicine, BK21 FOUR Program, Health & Life Convergence Sciences, Biomedical and Healthcare Research Institute, Mokpo National University, Muan, 58554, Republic of Korea
| | - Jinik Hwang
- West Sea Fisheries Research Institute, National Institute of Fisheries Science, Incheon, 22383, Republic of Korea
| | - Young Joon Oh
- Technology Innovation Research Division, World Institute of Kimchi, Gwangju, 61755, Republic of Korea
| | - Sung-Suk Suh
- Department of Biomedicine, BK21 FOUR Program, Health & Life Convergence Sciences, Biomedical and Healthcare Research Institute, Mokpo National University, Muan, 58554, Republic of Korea.
| | - Sung-Hak Kim
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea.
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Yao P, Xiao P, Huang Z, Tang M, Tang X, Yang G, Zhang Q, Li X, Yang Z, Xie C, Gong H, Wang G, Liu Y, Wang X, Li H, Jia D, Dai L, Chen L, Chen C, Liu Y, Xiao H, Zhang Y, Wang Y. Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues. NATURE CANCER 2023; 4:1176-1192. [PMID: 37537298 DOI: 10.1038/s43018-023-00608-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 06/29/2023] [Indexed: 08/05/2023]
Abstract
Detecting and targeting precancerous cells in noncancerous tissues is a major challenge for cancer prevention. Massive stabilization of mutant p53 (mutp53) proteins is a cancer-specific event that could potentially mark precancerous cells, yet in vivo protein-level mutp53 reporters are lacking. Here we developed two transgenic protein-level mutp53 reporters, p53R172H-Akaluc and p53-mCherry, that faithfully mimic the dynamics and function of mutp53 proteins in vivo. Using these reporters, we identified and traced rare precancerous clones in deep noncancerous tissues in various cancer models. In classic mutp53-driven thymic lymphoma models, we found that precancerous clones exhibit broad chromosome number variations, upregulate precancerous stage-specific genes such as Ybx3 and enhance amino acid transport and metabolism. Inhibiting amino acid transporters downstream of Ybx3 at the early but not late stage effectively suppresses tumorigenesis and prolongs survival. Together, these protein-level mutp53 reporters reveal undercharacterized features and vulnerabilities of precancerous cells during early tumorigenesis, paving the way for precision cancer prevention.
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Affiliation(s)
- Pengle Yao
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Xiao
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zongyao Huang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Min Tang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiwen Tang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Gaoxia Yang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qi Zhang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xinpei Li
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhengnan Yang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chuanxing Xie
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Gong
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Guihua Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China
| | - Yutong Liu
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiuxuan Wang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Huifang Li
- Core Facilities of West China Hospital, Sichuan University, Chengdu, China
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China
| | - Chong Chen
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Liu
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hengyi Xiao
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Zhang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Wang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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7
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Ocasio JK, Budd KM, Roach JT, Andrews JM, Baker SJ. Oncohistones and disrupted development in pediatric-type diffuse high-grade glioma. Cancer Metastasis Rev 2023; 42:367-388. [PMID: 37119408 PMCID: PMC10441521 DOI: 10.1007/s10555-023-10105-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/05/2023] [Indexed: 05/01/2023]
Abstract
Recurrent, clonal somatic mutations in histone H3 are molecular hallmarks that distinguish the genetic mechanisms underlying pediatric and adult high-grade glioma (HGG), define biological subgroups of diffuse glioma, and highlight connections between cancer, development, and epigenetics. These oncogenic mutations in histones, now termed "oncohistones", were discovered through genome-wide sequencing of pediatric diffuse high-grade glioma. Up to 80% of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) and diffuse glioma arising in other midline structures including thalamus or spinal cord, contain histone H3 lysine 27 to methionine (K27M) mutations or, rarely, other alterations that result in a depletion of H3K27me3 similar to that induced by H3 K27M. This subgroup of glioma is now defined as diffuse midline glioma, H3K27-altered. In contrast, histone H3 Gly34Arg/Val (G34R/V) mutations are found in approximately 30% of diffuse glioma arising in the cerebral hemispheres of older adolescents and young adults, now classified as diffuse hemispheric glioma, H3G34-mutant. Here, we review how oncohistones modulate the epigenome and discuss the mutational landscape and invasive properties of histone mutant HGGs of childhood. The distinct mechanisms through which oncohistones and other mutations rewrite the epigenetic landscape provide novel insights into development and tumorigenesis and may present unique vulnerabilities for pHGGs. Lessons learned from these rare incurable brain tumors of childhood may have broader implications for cancer, as additional high- and low-frequency oncohistone mutations have been identified in other tumor types.
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Affiliation(s)
- Jennifer K Ocasio
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Kaitlin M Budd
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA
- St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA
| | - Jordan T Roach
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA
- St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA
- College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Jared M Andrews
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Suzanne J Baker
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA.
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8
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Szu JI, Tsigelny IF, Wojcinski A, Kesari S. Biological functions of the Olig gene family in brain cancer and therapeutic targeting. Front Neurosci 2023; 17:1129434. [PMID: 37274223 PMCID: PMC10232966 DOI: 10.3389/fnins.2023.1129434] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 04/26/2023] [Indexed: 06/06/2023] Open
Abstract
The Olig genes encode members of the basic helix-loop-helix (bHLH) family of transcription factors. Olig1, Olig2, and Olig3 are expressed in both the developing and mature central nervous system (CNS) and regulate cellular specification and differentiation. Over the past decade extensive studies have established functional roles of Olig1 and Olig2 in development as well as in cancer. Olig2 overexpression drives glioma proliferation and resistance to radiation and chemotherapy. In this review, we summarize the biological functions of the Olig family in brain cancer and how targeting Olig family genes may have therapeutic benefit.
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Affiliation(s)
- Jenny I. Szu
- Department of Translational Neurosciences, Providence Saint John’s Health Center, Saint John’s Cancer Institute, Santa Monica, CA, United States
| | - Igor F. Tsigelny
- San Diego Supercomputer Center, University of California, San Diego, San Diego, CA, United States
- CureScience, San Diego, CA, United States
| | - Alexander Wojcinski
- Department of Translational Neurosciences, Providence Saint John’s Health Center, Saint John’s Cancer Institute, Santa Monica, CA, United States
- Pacific Neuroscience Institute, Santa Monica, CA, United States
| | - Santosh Kesari
- Department of Translational Neurosciences, Providence Saint John’s Health Center, Saint John’s Cancer Institute, Santa Monica, CA, United States
- Pacific Neuroscience Institute, Santa Monica, CA, United States
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9
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Mei N, Lu Y, Yang S, Jiang S, Ruan Z, Wang D, Liu X, Ying Y, Li X, Yin B. Oligodendrocyte Transcription Factor 2 as a Potential Prognostic Biomarker of Glioblastoma: Kaplan-Meier Analysis and the Development of a Binary Predictive Model Based on Visually Accessible Rembrandt Image and Magnetic Resonance Imaging Radiomic Features. J Comput Assist Tomogr 2023; Publish Ahead of Print:00004728-990000000-00157. [PMID: 37380154 DOI: 10.1097/rct.0000000000001454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
OBJECTIVE Oligodendrocyte transcription factor 2 (OLIG2) is universally expressed in human glioblastoma (GB). Our study explores whether OLIG2 expression impacts GB patients' overall survival and establishes a machine learning model for OLIG2 level prediction in patients with GB based on clinical, semantic, and magnetic resonance imaging radiomic features. METHODS Kaplan-Meier analysis was used to determine the optimal cutoff value of the OLIG2 in 168 GB patients. Three hundred thirteen patients enrolled in the OLIG2 prediction model were randomly divided into training and testing sets in a ratio of 7:3. The radiomic, semantic, and clinical features were collected for each patient. Recursive feature elimination (RFE) was used for feature selection. The random forest (RF) model was built and fine-tuned, and the area under the curve was calculated to evaluate the performance. Finally, a new testing set excluding IDH-mutant patients was built and tested in a predictive model using the fifth edition of the central nervous system tumor classification criteria. RESULTS One hundred nineteen patients were included in the survival analysis. Oligodendrocyte transcription factor 2 was positively associated with GB survival, with an optimal cutoff of 10% (P = 0.00093). One hundred thirty-four patients were eligible for the OLIG2 prediction model. An RFE-RF model based on 2 semantic and 21 radiomic signatures achieved areas under the curve of 0.854 in the training set, 0.819 in the testing set, and 0.825 in the new testing set. CONCLUSIONS Glioblastoma patients with ≤10% OLIG2 expression tended to have worse overall survival. An RFE-RF model integrating 23 features can predict the OLIG2 level of GB patients preoperatively, irrespective of the central nervous system classification criteria, further guiding individualized treatment.
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Affiliation(s)
- Nan Mei
- From the Departments of Radiology
| | | | | | | | | | | | - Xiujuan Liu
- Pathology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | | | | | - Bo Yin
- From the Departments of Radiology
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10
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Mandal AS, Brem S, Suckling J. Brain network mapping and glioma pathophysiology. Brain Commun 2023; 5:fcad040. [PMID: 36895956 PMCID: PMC9989143 DOI: 10.1093/braincomms/fcad040] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 12/23/2022] [Accepted: 02/18/2023] [Indexed: 02/25/2023] Open
Abstract
Adult diffuse gliomas are among the most difficult brain disorders to treat in part due to a lack of clarity regarding the anatomical origins and mechanisms of migration of the tumours. While the importance of studying networks of glioma spread has been recognized for at least 80 years, the ability to carry out such investigations in humans has emerged only recently. Here, we comprehensively review the fields of brain network mapping and glioma biology to provide a primer for investigators interested in merging these areas of inquiry for the purposes of translational research. Specifically, we trace the historical development of ideas in both brain network mapping and glioma biology, highlighting studies that explore clinical applications of network neuroscience, cells-of-origin of diffuse glioma and glioma-neuronal interactions. We discuss recent research that has merged neuro-oncology and network neuroscience, finding that the spatial distribution patterns of gliomas follow intrinsic functional and structural brain networks. Ultimately, we call for more contributions from network neuroimaging to realize the translational potential of cancer neuroscience.
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Affiliation(s)
- Ayan S Mandal
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, UK
| | - Steven Brem
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, Philadelphia, PA 19104, USA
| | - John Suckling
- Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, UK
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11
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Sanchez-Petidier M, Guerri C, Moreno-Manzano V. Toll-like receptors 2 and 4 differentially regulate the self-renewal and differentiation of spinal cord neural precursor cells. Stem Cell Res Ther 2022; 13:117. [PMID: 35314006 PMCID: PMC8935849 DOI: 10.1186/s13287-022-02798-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 03/07/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Toll-like receptors (TLRs) represent critical effectors in the host defense response against various pathogens; however, their known function during development has also highlighted a potential role in cell fate determination and neural differentiation. While glial cells and neural precursor cells (NPCs) of the spinal cord express both TLR2 and TLR4, their influence on self-renewal and cell differentiation remains incompletely described. METHODS TLR2, TLR4 knock-out and the wild type mice were employed for spinal cord tissue analysis and NPCs isolation at early post-natal stage. Sox2, FoxJ1 and Ki67 expression among others served to identify the undifferentiated and proliferative NPCs; GFAP, Olig2 and β-III-tubulin markers served to identify astrocytes, oligodendrocytes and neurons respectively after NPC spontaneous differentiation. Multiple comparisons were analyzed using one-way ANOVA, with appropriate corrections such as Tukey's post hoc tests used for comparisons. RESULTS We discovered that the deletion of TLR2 or TLR4 significantly reduced the number of Sox2-expressing NPCs in the neonatal mouse spinal cord. While TLR2-knockout NPCs displayed enhanced self-renewal, increased proliferation and apoptosis, and delayed neural differentiation, the absence of TLR4 promoted the neural differentiation of NPCs without affecting proliferation, producing long projecting neurons. TLR4 knock-out NPCs showed significantly higher expression of Neurogenin1, that would be involved in the activation of this neurogenic program by a ligand and microenvironment-independent mechanism. Interestingly, the absence of both TLR2 and TLR4, which induces also a significant reduction in the expression of TLR1, in NPCs impeded oligodendrocyte precursor cell maturation to a similar degree. CONCLUSIONS Our data suggest that Toll-like receptors are needed to maintain Sox2 positive neural progenitors in the spinal cord, however possess distinct regulatory roles in mouse neonatal spinal cord NPCs-while TLR2 and TLR4 play a similar role in oligodendrocytic differentiation, they differentially influence neural differentiation.
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Affiliation(s)
- Marina Sanchez-Petidier
- Neuronal and Tissue Regeneration Laboratory, Prince Felipe Research Institute, Valencia, Spain.,Neuropathology Laboratory, Prince Felipe Research Institute, Valencia, Spain
| | - Consuelo Guerri
- Neuropathology Laboratory, Prince Felipe Research Institute, Valencia, Spain.
| | - Victoria Moreno-Manzano
- Neuronal and Tissue Regeneration Laboratory, Prince Felipe Research Institute, Valencia, Spain.
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12
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The Epigenetic Regulation of OLIG2 by Histone Demethylase KDM6B in Glioma Cells. J Mol Neurosci 2022; 72:939-946. [DOI: 10.1007/s12031-022-01976-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/16/2022] [Indexed: 11/30/2022]
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13
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Sasai K, Tabu K, Saito T, Matsuba Y, Saido TC, Tanaka S. Difference in the malignancy between RAS and GLI1-transformed astrocytes is associated with frequency of p27 KIP1-positive cells in xenograft tissues. Pathol Res Pract 2021; 223:153465. [PMID: 33989885 DOI: 10.1016/j.prp.2021.153465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/02/2021] [Accepted: 05/02/2021] [Indexed: 10/21/2022]
Abstract
We demonstrate that the introduction of GLI1 is sufficient for immortalized human astrocytes to be transformed whereas FOXM1 fails to induce malignant transformation, suggesting differences between GLI1 and FOXM1 in terms of transforming ability despite both transcription factors being overexpressed in malignant gliomas. Moreover, in investigations of mechanisms underlying relatively less-malignant features of GLI1-transformed astrocytes, we found that p27KIP1-positive cells were frequently observed in xenografts derived from GLI1-transformed astrocytes compared to those from RAS-transformed cells. As shRNA-mediated knockdown of p27KIP1 accelerates tumor progression of GLI1-transformed astrocytes, downregulation of p27KIP1 contributes to malignant features of transformed astrocytes. We propose that the models using immortalized/transformed astrocytes are useful to identify the minimal and most crucial set of changes required for glioma formation.
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Affiliation(s)
- Ken Sasai
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo, 060-8638, Japan.
| | - Kouichi Tabu
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo, 060-8638, Japan
| | - Takashi Saito
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Yukio Matsuba
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Takaomi C Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo, 060-8638, Japan; WPI Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, N21 W10, Kita-ku, Sapporo, 001-0021, Japan
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14
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Curry RN, Glasgow SM. The Role of Neurodevelopmental Pathways in Brain Tumors. Front Cell Dev Biol 2021; 9:659055. [PMID: 34012965 PMCID: PMC8127784 DOI: 10.3389/fcell.2021.659055] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Disruptions to developmental cell signaling pathways and transcriptional cascades have been implicated in tumor initiation, maintenance and progression. Resurgence of aberrant neurodevelopmental programs in the context of brain tumors highlights the numerous parallels that exist between developmental and oncologic mechanisms. A deeper understanding of how dysregulated developmental factors contribute to brain tumor oncogenesis and disease progression will help to identify potential therapeutic targets for these malignancies. In this review, we summarize the current literature concerning developmental signaling cascades and neurodevelopmentally-regulated transcriptional programs. We also examine their respective contributions towards tumor initiation, maintenance, and progression in both pediatric and adult brain tumors and highlight relevant differentiation therapies and putative candidates for prospective treatments.
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Affiliation(s)
- Rachel N. Curry
- Department of Neuroscience, Baylor College of Medicine, Center for Cell and Gene Therapy, Houston, TX, United States
- Integrative Molecular and Biomedical Sciences, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX, United States
| | - Stacey M. Glasgow
- Neurobiology Section, Division of Biological Sciences, University of California, San Diego, San Diego, CA, United States
- Neurosciences Graduate Program, University of California, San Diego, San Diego, CA, United States
- Biomedical Sciences Graduate Program, University of California, San Diego, San Diego, CA, United States
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15
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Chan JL, Kashanian A, Bannykh SI, Majlessipour F, Breunig JJ, Danielpour M. RELA Fusion-Positive Ependymoma in a Child with Down Syndrome: A Case Report. Pediatr Neurosurg 2021; 56:146-151. [PMID: 33690230 DOI: 10.1159/000511673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 09/12/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Down syndrome (DS) is the most common multiple malformation syndrome in humans and is associated with an increased risk of childhood malignancy, particularly leukemia. Incidence of brain tumors in patients with DS is limited to sporadic cases. We report the first case of a RELA fusion-positive ependymoma in a 3-year-old boy with DS. CASE PRESENTATION Imaging prompted by new left-sided hemiparesis demonstrated an 8-cm hemorrhagic right temporal-parietal mass. Subsequent image-complete resection confirmed a RELA fusion-positive anaplastic ependymoma with 90% OLIG2 staining. Postoperatively, the patient, unfortunately, experienced fatal recurrence and drop metastases with leptomeningeal involvement. CONCLUSION To our knowledge, this is the first reported case of a confirmed RELA fusion-positive ependymoma in a child with DS. We discuss this finding in the context of intracranial tumors in children with DS, as well as the finding of 90% positive OLIG2 expression and its potential as a prognostic marker.
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Affiliation(s)
- Julie L Chan
- Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Alon Kashanian
- Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Serguei I Bannykh
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Fataneh Majlessipour
- Department of Pediatric Hematology and Oncology, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Joshua J Breunig
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Moise Danielpour
- Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA,
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16
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Arthur-Farraj P, Moyon S. DNA methylation in Schwann cells and in oligodendrocytes. Glia 2020; 68:1568-1583. [PMID: 31958184 DOI: 10.1002/glia.23784] [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] [Received: 10/17/2019] [Revised: 12/17/2019] [Accepted: 01/10/2020] [Indexed: 12/12/2022]
Abstract
DNA methylation is one of many epigenetic marks, which directly modifies base residues, usually cytosines, in a multiple-step cycle. It has been linked to the regulation of gene expression and alternative splicing in several cell types, including during cell lineage specification and differentiation processes. DNA methylation changes have also been observed during aging, and aberrant methylation patterns have been reported in several neurological diseases. We here review the role of DNA methylation in Schwann cells and oligodendrocytes, the myelin-forming glia of the peripheral and central nervous systems, respectively. We first address how methylation and demethylation are regulating myelinating cells' differentiation during development and repair. We then mention how DNA methylation dysregulation in diseases and cancers could explain their pathogenesis by directly influencing myelinating cells' proliferation and differentiation capacities.
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Affiliation(s)
- Peter Arthur-Farraj
- John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Sarah Moyon
- Neuroscience Initiative Advanced Science Research Center, CUNY, New York, New York
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17
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A rare case of oligodendroglioma with gangliocytic differentiation in a 31-year-old male: importance of genetic testing for IDH1/2. Brain Tumor Pathol 2020; 37:95-99. [PMID: 32504153 DOI: 10.1007/s10014-020-00368-w] [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: 05/05/2020] [Accepted: 05/24/2020] [Indexed: 10/24/2022]
Abstract
We report a rare case of oligodendroglioma with gangliocytic differentiation. A 31-year-old male without a past medical history was admitted with a sudden seizure. On magnetic resonance imaging, an approximately 7-cm mass with necrosis was noted in the right frontal lobe. The patient underwent surgical resection. On microscopy, two morphologically distinct areas with oligodendroglioma- and ganglioglioma-like features were found. Immunohistochemistry showed an absence of CD34 expression, whereas isocitrate dehydrogenase 1 (IDH1) was positive in the glial component. Moreover, IDH1 was positive in the ganglion-like cells as well as in the glial component. Subsequent 1p/19q co-deletion was confirmed by fluorescence in situ hybridization. Finally, a diagnosis of oligodendroglioma with gangliocytic differentiation was made. IDH1/2 molecular test would be basic and essential diagnostic tool in central nervous system tumor of young patients.
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18
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Panagopoulos I, Gorunova L, Johannsdottir IMR, Andersen K, Holth A, Beiske K, Heim S. Chromosome Translocation t(14;21)(q11;q22) Activates Both OLIG1 and OLIG2 in Pediatric T-cell Lymphoblastic Malignancies and May Signify Adverse Prognosis. Cancer Genomics Proteomics 2020; 17:41-48. [PMID: 31882550 DOI: 10.21873/cgp.20166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 11/11/2019] [Accepted: 11/15/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM The chromosome translocation t(14;21)(q11;q22) was reported in four pediatric T-cell lymphoblastic leukemias and was shown to activate the OLIG2 gene. MATERIALS AND METHODS A pediatric T-cell lymphoblastic lymphoma was investigated using G-banding chromosome analysis, fluorescence in situ hybridization (FISH), and immunocytochemistry. RESULTS The malignant cells carried a t(14;21)(q11;q22) aberration. The translocation moves the enhancer elements of TRA/TRD from band 14q11 to 21q22, a few thousands kbp downstream of OLIG1 and OLIG2, resulting in the production of both OLIG1 and OLIG2 proteins. CONCLUSION The translocation t(14;21)(q11;q22) occurs in some pediatric T-cell lymphoblastic malignancies. Activation of both OLIG1 and OLIG2 by t(14;21)(q11;q22) in T-lymphoblasts and the ensuing deregulation of thousands of genes could explain the highly malignant disease and resistance to treatment that has characterized this small group of patients.
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Affiliation(s)
- Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ludmila Gorunova
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Inga Maria Rinvoll Johannsdottir
- Department of Pediatric Cancer and Blood Disorders, Oslo University Hospital, Oslo, Norway.,National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, Oslo, Norway
| | - Kristin Andersen
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Arild Holth
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Klaus Beiske
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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19
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Li L, Maire CL, Bilenky M, Carles A, Heravi-Moussavi A, Hong C, Tam A, Kamoh B, Cho S, Cheung D, Li I, Wong T, Nagarajan RP, Mungall AJ, Moore R, Wang T, Kleinman CL, Jabado N, Jones SJM, Marra MA, Ligon KL, Costello JF, Hirst M. Epigenomic programming in early fetal brain development. Epigenomics 2020; 12:1053-1070. [PMID: 32677466 PMCID: PMC7857341 DOI: 10.2217/epi-2019-0319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 03/19/2020] [Indexed: 12/21/2022] Open
Abstract
Aim: To provide a comprehensive understanding of gene regulatory networks in the developing human brain and a foundation for interpreting pathogenic deregulation. Materials & methods: We generated reference epigenomes and transcriptomes of dissected brain regions and primary neural progenitor cells (NPCs) derived from cortical and ganglionic eminence tissues of four normal human fetuses. Results: Integration of these data across developmental stages revealed a directional increase in active regulatory states, transcription factor activities and gene transcription with developmental stage. Consistent with differences in their biology, NPCs derived from cortical and ganglionic eminence regions contained common, region specific, and gestational week specific regulatory states. Conclusion: We provide a high-resolution regulatory network for NPCs from different brain regions as a comprehensive reference for future studies.
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Affiliation(s)
- Luolan Li
- Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Cecile L Maire
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Misha Bilenky
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Annaïck Carles
- Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | | | - Chibo Hong
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | - Angela Tam
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Baljit Kamoh
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Stephanie Cho
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Dorothy Cheung
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Irene Li
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Tina Wong
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Raman P Nagarajan
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | - Andrew J Mungall
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Richard Moore
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Ting Wang
- Department of Genetics, Washington University, St Louis, MO 63108, USA
| | - Claudia L Kleinman
- Department of Human Genetics, McGill University, Montreal, QC, H3T 1E2, Canada
| | - Nada Jabado
- Department of Human Genetics, McGill University, Montreal, QC, H3T 1E2, Canada
| | - Steven JM Jones
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada
| | - Keith L Ligon
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Joseph F Costello
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | - Martin Hirst
- Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
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20
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Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting. Cell Death Differ 2020; 27:3146-3161. [PMID: 32483381 PMCID: PMC7560653 DOI: 10.1038/s41418-020-0569-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 01/05/2023] Open
Abstract
Posttranslational modifications of nuclear proteins, including transcription factors, nuclear receptors, and their coregulators, have attracted much attention in cancer research. Although phosphorylation of oligodendrocyte transcription factor 2 (Olig2) may contribute to the notorious resistance of gliomas to radiation and genotoxic drugs, the precise mechanisms remain elusive. We show here that in addition to phosphorylation, Olig2 is also conjugated by small ubiquitin-like modifier-1 (SUMO1) at three lysine residues K27, K76, and K112. SUMOylation is required for Olig2 to suppress p53-mediated cell cycle arrest and apoptosis induced by genotoxic damage, and to enhance resistance to temozolomide (TMZ) in glioma. Both SUMOylation and triple serine motif (TSM) phosphorylation of Olig2 are required for the antiapoptotic function. Olig2 SUMOylation enhances its genetic targeting ability, which in turn occludes p53 recruitment to Cdkn1a promoter for DNA-damage responses. Our work uncovers a SUMOylation-dependent regulatory mechanism of Olig2 in regulating cancer survival.
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21
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Bouchart C, Trépant AL, Hein M, Van Gestel D, Demetter P. Prognostic impact of glioblastoma stem cell markers OLIG2 and CCND2. Cancer Med 2019; 9:1069-1078. [PMID: 31568682 PMCID: PMC6997071 DOI: 10.1002/cam4.2592] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/06/2019] [Accepted: 09/16/2019] [Indexed: 12/28/2022] Open
Abstract
Aims Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults. Glioma stem cells (GSCs) are implicated in this poor prognosis and in radio(chemo‐)resistance. We have previously demonstrated that among potentially highly specific GSC markers oligodendrocyte lineage transcription factor 2 (OLIG2) appears to be the most specific and cyclin D2 (CCND2) the only one related to cell cycle regulation. The purpose of this work was to investigate the clinical significance and the evolution of OLIG2 and CCND2 protein expression in GBM. Methods and results Immunohistochemical expression analysis of Olig2 and Ccnd2 was carried out on a cohort of human paired GBM samples comparing initial resections with local recurrent tumors after radiation therapy (RT) alone or radio‐chemotherapy with temozolomide (RT‐TMZ). Uni‐ and multivariate logistic regression analysis revealed that significant risk factors predicting early mortality (<12 months) are: subtotal surgery for recurrence, time to recurrence <6 months, Ccnd2 nuclear expression at initial surgery ≥30%, and Olig2 nuclear expression <30% at second surgery after RT alone and RT‐TMZ. Conclusions We demonstrated that patients for whom nuclear expression of Olig2 becomes low (<30%) after adjuvant treatments have a significantly shorter time to recurrence and survival reflecting most probably a proneural to mesenchymal transition of the GSCs population. We also highlighted the fact that at initial surgery, high nuclear expression (≥30%) of CCND2, a G1/S regulator specific of GSCs, has a prognostic value and is associated with early mortality (<12 months).
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Affiliation(s)
- Christelle Bouchart
- Department of Radiation-Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Anne-Laure Trépant
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Matthieu Hein
- Department of Psychiatry and Sleep Laboratory, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Dirk Van Gestel
- Department of Radiation-Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Pieter Demetter
- Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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22
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Choudhury S. Genomics of the OLIG family of a bHLH transcription factor associated with oligo dendrogenesis. Bioinformation 2019; 15:430-438. [PMID: 31312081 PMCID: PMC6614118 DOI: 10.6026/97320630015430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 01/07/2019] [Indexed: 01/28/2023] Open
Abstract
The glial cell neoplasms are not fully classified by using cellular morphology. However, this is possible using known molecular markers in glial development. Oligo-dendrocyte lineage gene induces differentiation of neural progenitors and putative immature progenitor cells of the adult central nervous system. These oligo-dendrocyte lineage genes OLIG1 and OLIG2 encode basic helix-loop-helix transcription factors. The murine bHLH transcription factors found in chromosome 21 are essential for oligo-dendrocyte development. Moreover, OLIG3 of the OLIG family is known to be linked with the brain and spinal cord development. Therefore, it is of interest to analyse oligodendrocyte lineage genes in the OLIG family of bHLH domain for the understanding of oligo-dendrogenesis in eukaryotes. Several bHLH domain linked basic-helix-loop-helix transcription factors in Homo sapiens and Mus musculus from this analysis are reported. Thus, genomics data analysis of OLIG family of bHLH transcription factors help explain observed similarity and differences within the molecular evolutionary context and hence assess the functional significance of the distinct genetic blueprints.
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23
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Lu QR, Qian L, Zhou X. Developmental origins and oncogenic pathways in malignant brain tumors. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2019; 8:e342. [PMID: 30945456 DOI: 10.1002/wdev.342] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/20/2019] [Accepted: 03/08/2019] [Indexed: 12/21/2022]
Abstract
Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Signaling Pathways > Cell Fate Signaling.
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Affiliation(s)
- Q Richard Lu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Lily Qian
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Xianyao Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Sichuan University, Chengdu, China.,Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
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24
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Rahme GJ, Luikart BW, Cheng C, Israel MA. A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma. Neuro Oncol 2019; 20:332-342. [PMID: 29016807 DOI: 10.1093/neuonc/nox129] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma. Methods We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells. Results The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature. Conclusion Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics.
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Affiliation(s)
- Gilbert J Rahme
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.,Norris Cotton Cancer Center, Dartmouth, Hanover, New Hampshire.,Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Bryan W Luikart
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.,Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Chao Cheng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.,Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Mark A Israel
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.,Department of Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.,Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.,Norris Cotton Cancer Center, Dartmouth, Hanover, New Hampshire.,Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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25
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Yuan T, York JR, McCauley DW. Gliogenesis in lampreys shares gene regulatory interactions with oligodendrocyte development in jawed vertebrates. Dev Biol 2018; 441:176-190. [DOI: 10.1016/j.ydbio.2018.07.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 07/02/2018] [Accepted: 07/02/2018] [Indexed: 01/09/2023]
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26
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Dennis DJ, Han S, Schuurmans C. bHLH transcription factors in neural development, disease, and reprogramming. Brain Res 2018; 1705:48-65. [PMID: 29544733 DOI: 10.1016/j.brainres.2018.03.013] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 03/07/2018] [Accepted: 03/10/2018] [Indexed: 01/16/2023]
Abstract
The formation of functional neural circuits in the vertebrate central nervous system (CNS) requires that appropriate numbers of the correct types of neuronal and glial cells are generated in their proper places and times during development. In the embryonic CNS, multipotent progenitor cells first acquire regional identities, and then undergo precisely choreographed temporal identity transitions (i.e. time-dependent changes in their identity) that determine how many neuronal and glial cells of each type they will generate. Transcription factors of the basic-helix-loop-helix (bHLH) family have emerged as key determinants of neural cell fate specification and differentiation, ensuring that appropriate numbers of specific neuronal and glial cell types are produced. Recent studies have further revealed that the functions of these bHLH factors are strictly regulated. Given their essential developmental roles, it is not surprising that bHLH mutations and de-regulated expression are associated with various neurological diseases and cancers. Moreover, the powerful ability of bHLH factors to direct neuronal and glial cell fate specification and differentiation has been exploited in the relatively new field of cellular reprogramming, in which pluripotent stem cells or somatic stem cells are converted to neural lineages, often with a transcription factor-based lineage conversion strategy that includes one or more of the bHLH genes. These concepts are reviewed herein.
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Affiliation(s)
- Daniel J Dennis
- Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, ON M4N3M5, Canada
| | - Sisu Han
- Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, ON M4N3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Carol Schuurmans
- Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, ON M4N3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
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27
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Hide T, Komohara Y, Miyasato Y, Nakamura H, Makino K, Takeya M, Kuratsu JI, Mukasa A, Yano S. Oligodendrocyte Progenitor Cells and Macrophages/Microglia Produce Glioma Stem Cell Niches at the Tumor Border. EBioMedicine 2018; 30:94-104. [PMID: 29559295 PMCID: PMC5952226 DOI: 10.1016/j.ebiom.2018.02.024] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 02/19/2018] [Accepted: 02/28/2018] [Indexed: 01/23/2023] Open
Abstract
Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a promising target for prevention of recurrence.
Most cases of glioblastoma recur in white matter around the removal cavity after total resection plus chemo-radiotherapy. miRNAs showing characteristically higher expression in the tumor border were related to oligodendrocyte differentiation. Increased oligodendrocyte progenitor cells and macrophages enhance stemness and chemo-radioresistance in glioma cells. Glioblastoma (GBM) occurs in adult brain and shows rapid growth and invasion. Despite intensive treatment, the mean 5-year survival rate is still <10%. Most cases of GBM recur locally even after total resection of gadolinium-enhanced lesions observed with MRI, indicating that chemo-radioresistant GBM cells survive there. MicroRNAs showing characteristically higher expression in the tumor border were related to oligodendrocyte differentiation. Oligodendrocyte progenitor cells (OPCs) and macrophages/microglia increased at tumor borders, and induced stemness and chemo-radioresistance in GBM cells in vivo. Thus, OPCs and macrophages/microglia formed characteristic microenvironments and may be promising targets to prevent GBM recurrence.
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Affiliation(s)
- Takuichiro Hide
- Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Japan.
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Yuko Miyasato
- Department of Cell Pathology, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Hideo Nakamura
- Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Keishi Makino
- Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Motohiro Takeya
- Department of Cell Pathology, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Jun-Ichi Kuratsu
- Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Akitake Mukasa
- Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Japan
| | - Shigetoshi Yano
- Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Japan
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28
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Mehta S, Lo Cascio C. Developmentally regulated signaling pathways in glioma invasion. Cell Mol Life Sci 2018; 75:385-402. [PMID: 28821904 PMCID: PMC5765207 DOI: 10.1007/s00018-017-2608-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 07/18/2017] [Accepted: 08/03/2017] [Indexed: 01/06/2023]
Abstract
Malignant gliomas are the most common, infiltrative, and lethal primary brain tumors affecting the adult population. The grim prognosis for this disease is due to a combination of the presence of highly invasive tumor cells that escape surgical resection and the presence of a population of therapy-resistant cancer stem cells found within these tumors. Several studies suggest that glioma cells have cleverly hijacked the normal developmental program of neural progenitor cells, including their transcriptional programs, to enhance gliomagenesis. In this review, we summarize the role of developmentally regulated signaling pathways that have been found to facilitate glioma growth and invasion. Furthermore, we discuss how the microenvironment and treatment-induced perturbations of these highly interconnected signaling networks can trigger a shift in cellular phenotype and tumor subtype.
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Affiliation(s)
- Shwetal Mehta
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ, 85013, USA.
| | - Costanza Lo Cascio
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ, 85013, USA
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29
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Schwab DE, Lepski G, Borchers C, Trautmann K, Paulsen F, Schittenhelm J. Immunohistochemical comparative analysis of GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 expression in WHO 2016 classified neuroepithelial tumours and their prognostic value. Pathol Res Pract 2017; 214:15-24. [PMID: 29258767 DOI: 10.1016/j.prp.2017.12.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/01/2017] [Accepted: 12/11/2017] [Indexed: 12/14/2022]
Abstract
Immunohistochemistry is routinely used in differential diagnosis of tumours of the central nervous system (CNS). The latest 2016 WHO 2016 revision now includes molecular data such as IDH mutation and 1p/19q codeletion thus restructuring glioma classification. Direct comparative information between commonly used immunohistochemical markers for glial tumours GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 concerning quality and quantity of expression and their relation to the new molecular markers are lacking. We therefore compared the immunohistochemical staining results of all five antibodies in 34 oligodendrogliomas, 106 ependymomas and 423 astrocytic tumours. GFAP expression was reduced in cases with higher WHO grade, oligodendroglial differentiation and in IDH wildtype diffuse astrocytomas. By contrast MAP - 2 expression was significantly increased in diffuse astrocytomas with IDH mutation, while NOGO - A expression was not associated with any molecular marker. WT - 1 expression was significantly decreased in tumours with IDH mutation and ATRX loss. OLIG - 2 was increased in IDH-mutant grade II astrocytomas and in cases with higher proliferation rate. In univariate survival analysis high WT - 1 expression was significantly associated with worse outcome in diffuse astrocytic tumours (log rank p < 0.0001; n = 211; median time: 280 days vs 562 days). None of the markers was prognostic in multivariate survival analysis. Among the evaluated markers MAP - 2, OLIG - 2 and WT - 1 showed the best potential to separate between glioma entities and can be recommended for a standardized immunohistochemical panel.
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Affiliation(s)
- David Emanuel Schwab
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen and Comprehensive Cancer Center Tuebingen-Stuttgart, Tuebingen, 72076, Germany
| | - Guilherme Lepski
- Department of Neurosurgery, University Hospital of Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, 72076, Germany
| | - Christian Borchers
- Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
| | - Katrin Trautmann
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen and Comprehensive Cancer Center Tuebingen-Stuttgart, Tuebingen, 72076, Germany
| | - Frank Paulsen
- Department of Radiation Oncology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen and Comprehensive Cancer Center Tuebingen-Stuttgart, Tuebingen, 72076, Germany
| | - Jens Schittenhelm
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen and Comprehensive Cancer Center Tuebingen-Stuttgart, Tuebingen, 72076, Germany.
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30
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Schäfer S, Behling F, Skardelly M, Koch M, Ott I, Paulsen F, Tabatabai G, Schittenhelm J. Low FoxG1 and high Olig-2 labelling indices define a prognostically favourable subset in isocitrate dehydrogenase (IDH)-mutant gliomas. Neuropathol Appl Neurobiol 2017; 44:207-223. [PMID: 29053887 DOI: 10.1111/nan.12447] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 10/12/2017] [Indexed: 11/30/2022]
Abstract
AIMS Previous data suggest that expression of transcription factors FoxG1 and Olig-2 can separate hotspot histone H3 family member 3A (H3F3A)-mutant tumours in paediatric glioma. We evaluated their prognostic potential and feasibility for identifying H3F3A-mutant tumours among IDH-mutant/wild-type gliomas. METHODS Immunohistochemistry of FoxG1/Olig-2 and α-thalassaemia/mental-retardation-syndrome-X-linked gene (ATRX) in 471 cases of diffuse gliomas and molecular determination of IDH, H3F3A, MGMT and 1p/19 codeletion status. RESULTS Mean percentage of FoxG1-positive tumour cells increased from 17% in WHO grade II to over 21% in grade III to 37% in grade IV tumours, whereas mean Olig-2 indices decreased from 29% to 28% to 17% respectively. FoxG1 indices were similar in astrocytic and oligodendroglial tumours, whereas Olig-2 indices were increased in oligodendrogliomas compared to astrocytic tumours (n = 451, P < 0.0001). FoxG1-positive nuclei were significantly reduced in IDH and H3F3A K27-mutant tumours, whereas Olig-2-positive nuclei were significantly reduced in IDH-wild-type and H3F3A G34-mutant tumours. Among IDH-mutant tumours, mean Olig-2 index was significantly higher in 1p/19q codeleted tumours (mean: 43%) compared to IDH-mutant tumours with ATRX loss (mean: 23%, P < 0.0001). A significantly better outcome was first suggested for FoxG1low tumours (n = 212, log rank P = 0.0132) and Olig-2high tumours (n = 203, log-rank P = 0.0011) based on classification and regression tree determined cutoffs, but this was not confirmed by multivariate analysis including IDH mutation, WHO grade, ATRX status and age. CONCLUSIONS While the combined FoxG1/Olig-2 profile may discriminate H3F3A K27- and G34-mutant tumours and define a prognostically favourable subset in IDH-mutant gliomas, our data show that labelling indices of these transcription factors overlap with adult IDH-mutant and wild-type tumour classes.
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Affiliation(s)
- S Schäfer
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - F Behling
- Department of Neurosurgery, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - M Skardelly
- Department of Neurosurgery, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - M Koch
- Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Interdisciplinary Division of Neurooncology, Departments of Vascular Neurology & Neurosurgery, Hertie Institute for Clinical Brain Research, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Center for Personalized Medicine, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,German Consortium for Translational Cancer Research (DKTK), DKFZ partner site Tuebingen, Tuebingen, Germany
| | - I Ott
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - F Paulsen
- Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Department of Radiation Oncology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - G Tabatabai
- Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Interdisciplinary Division of Neurooncology, Departments of Vascular Neurology & Neurosurgery, Hertie Institute for Clinical Brain Research, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Center for Personalized Medicine, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,German Consortium for Translational Cancer Research (DKTK), DKFZ partner site Tuebingen, Tuebingen, Germany
| | - J Schittenhelm
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
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31
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A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Rep 2017; 18:3167-3177. [PMID: 28355568 DOI: 10.1016/j.celrep.2017.03.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 11/14/2016] [Accepted: 02/28/2017] [Indexed: 11/22/2022] Open
Abstract
During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3α/β [GSK3α/β], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged "acid blob" in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics.
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32
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Zhao D, Lin M, Pedrosa E, Lachman HM, Zheng D. Characteristics of allelic gene expression in human brain cells from single-cell RNA-seq data analysis. BMC Genomics 2017; 18:860. [PMID: 29126398 PMCID: PMC5681780 DOI: 10.1186/s12864-017-4261-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 11/01/2017] [Indexed: 12/24/2022] Open
Abstract
Background Monoallelic expression of autosomal genes has been implicated in human psychiatric disorders. However, there is a paucity of allelic expression studies in human brain cells at the single cell and genome wide levels. Results In this report, we reanalyzed a previously published single-cell RNA-seq dataset from several postmortem human brains and observed pervasive monoallelic expression in individual cells, largely in a random manner. Examining single nucleotide variants with a predicted functional disruption, we found that the “damaged” alleles were overall expressed in fewer brain cells than their counterparts, and at a lower level in cells where their expression was detected. We also identified many brain cell type-specific monoallelically expressed genes. Interestingly, many of these cell type-specific monoallelically expressed genes were enriched for functions important for those brain cell types. In addition, function analysis showed that genes displaying monoallelic expression and correlated expression across neuronal cells from different individual brains were implicated in the regulation of synaptic function. Conclusions Our findings suggest that monoallelic gene expression is prevalent in human brain cells, which may play a role in generating cellular identity and neuronal diversity and thus increasing the complexity and diversity of brain cell functions. Electronic supplementary material The online version of this article (10.1186/s12864-017-4261-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dejian Zhao
- Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA
| | - Mingyan Lin
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Present address: Department of Neuroscience, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, 21166, China
| | - Erika Pedrosa
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA
| | - Herbert M Lachman
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.,Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA
| | - Deyou Zheng
- Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA. .,Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA. .,Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, USA.
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33
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Kosty J, Lu F, Kupp R, Mehta S, Lu QR. Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas. Cell Cycle 2017; 16:1654-1660. [PMID: 28806136 DOI: 10.1080/15384101.2017.1361062] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRα downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRα, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas.
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Affiliation(s)
- Jennifer Kosty
- a Department of Pediatrics, Divisions of Experimental Hematology and Cancer Biology & Developmental Biology, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.,b Department of Neurosurgery , University of Cincinnati , Cincinnati , OH , USA
| | - Fanghui Lu
- a Department of Pediatrics, Divisions of Experimental Hematology and Cancer Biology & Developmental Biology, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.,c National Centre for International Research in Cell and Gene Therapy, Centre for Cell and Gene Therapy of Academy of Medical Sciences , Zhengzhou University , Zhengzhou , Henan , China
| | - Robert Kupp
- d Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center , Phoenix , AZ , USA.,e Cancer Research UK Cambridge Institute , University of Cambridge, Li Ka Shing Centre , Cambridge , UK
| | - Shwetal Mehta
- d Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center , Phoenix , AZ , USA
| | - Q Richard Lu
- a Department of Pediatrics, Divisions of Experimental Hematology and Cancer Biology & Developmental Biology, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA
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Tan BT, Jiang L, Liu L, Yin Y, Luo ZRX, Long ZY, Li S, Yu LH, Wu YM, Liu Y. Local injection of Lenti-Olig2 at lesion site promotes functional recovery of spinal cord injury in rats. CNS Neurosci Ther 2017; 23:475-487. [PMID: 28452182 DOI: 10.1111/cns.12694] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 03/08/2017] [Accepted: 03/10/2017] [Indexed: 12/17/2022] Open
Abstract
AIMS Olig2 is one of the most critical factors during CNS development, which belongs to b-HLH transcription factor family. Previous reports have shown that Olig2 regulates the remyelination processes in CNS demyelination diseases models. However, the role of Olig2 in contusion spinal cord injury (SCI) and the possible therapeutic effects remain obscure. This study aims to investigate the effects of overexpression Olig2 by lentivirus on adult spinal cord injury rats. METHODS Lenti-Olig2 expression and control Lenti-eGFP vectors were prepared, and virus in a total of 5 μL (108 TU/mL) was locally injected into the injured spinal cord 1.5 mm rostral and caudal near the epicenter. Immunostaining, Western blot, electron microscopy, and CatWalk analyzes were employed to investigate the effects of Olig2 on spinal cord tissue repair and functional recovery. RESULTS Injection of Lenti-Olig2 significantly increased the number of oligodendrocytes lineage cells and enhanced myelination after SCI. More importantly, the introduction of Olig2 greatly improved hindlimb locomotor performances. Other oligodendrocyte-related transcription factors, which were downregulated or upregulated after injury, were reversed by Olig2 induction. CONCLUSIONS Our findings provided the evidence that overexpression Olig2 promotes myelination and locomotor recovery of contusion SCI, which gives us more understanding of Olig2 on spinal cord injury treatment.
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Affiliation(s)
- Bo-Tao Tan
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China.,Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Long Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Li Liu
- Department of Brain, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Ying Yin
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ze-Ru-Xin Luo
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zai-Yun Long
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Sen Li
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Le-Hua Yu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ya-Min Wu
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Yuan Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China
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35
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Tsigelny IF, Kouznetsova VL, Lian N, Kesari S. Molecular mechanisms of OLIG2 transcription factor in brain cancer. Oncotarget 2016; 7:53074-53101. [PMID: 27447975 PMCID: PMC5288170 DOI: 10.18632/oncotarget.10628] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 06/03/2016] [Indexed: 12/13/2022] Open
Abstract
Oligodendrocyte lineage transcription factor 2 (OLIG2) plays a pivotal role in glioma development. Here we conducted a comprehensive study of the critical gene regulatory networks involving OLIG2. These include the networks responsible for OLIG2 expression, its translocation to nucleus, cell cycle, epigenetic regulation, and Rho-pathway interactions. We described positive feedback loops including OLIG2: loops of epigenetic regulation and loops involving receptor tyrosine kinases. These loops may be responsible for the prolonged oncogenic activity of OLIG2. The proposed schemes for epigenetic regulation of the gene networks involving OLIG2 are confirmed by patient survival (Kaplan-Meier) curves based on the cancer genome atlas (TCGA) datasets. Finally, we elucidate the Coherent-Gene Modules (CGMs) networks-framework of OLIG2 involvement in cancer. We showed that genes interacting with OLIG2 formed eight CGMs having a set of intermodular connections. We showed also that among the genes involved in these modules the most connected hub is EGFR, then, on lower level, HSP90 and CALM1, followed by three lower levels including epigenetic genes KDM1A and NCOR1. The genes on the six upper levels of the hierarchy are involved in interconnections of all eight CGMs and organize functionally defined gene-signaling subnetworks having specific functions. For example, CGM1 is involved in epigenetic control. CGM2 is significantly related to cell proliferation and differentiation. CGM3 includes a number of interconnected helix-loop-helix transcription factors (bHLH) including OLIG2. Many of these TFs are partially controlled by OLIG2. The CGM4 is involved in PDGF-related: angiogenesis, tumor cell proliferation and differentiation. These analyses provide testable hypotheses and approaches to inhibit OLIG2 pathway and relevant feed-forward and feedback loops to be interrogated. This broad approach can be applied to other TFs.
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Affiliation(s)
- Igor F. Tsigelny
- Department of Neurosciences, University of California San Diego, La Jolla, 92093-0752, CA, USA
- San Diego Supercomputer Center, University of California San Diego, La Jolla, 92093-0505, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, 92093, CA, USA
| | - Valentina L. Kouznetsova
- San Diego Supercomputer Center, University of California San Diego, La Jolla, 92093-0505, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, 92093, CA, USA
| | - Nathan Lian
- REHS, San Diego Supercomputer Center, University of California San Diego, La Jolla, 92093-0505, CA, USA
| | - Santosh Kesari
- John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, 90404, CA, USA
- Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, 90404, CA, USA
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36
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Rahimi M, Vinciguerra M, Daghighi M, Özcan B, Akbarkhanzadeh V, Sheedfar F, Amini M, Mazza T, Pazienza V, Motazacker MM, Mahmoudi M, De Rooij FWM, Sijbrands E, Peppelenbosch MP, Rezaee F. Age-related obesity and type 2 diabetes dysregulate neuronal associated genes and proteins in humans. Oncotarget 2016; 6:29818-32. [PMID: 26337083 PMCID: PMC4745765 DOI: 10.18632/oncotarget.4904] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 08/07/2015] [Indexed: 12/29/2022] Open
Abstract
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
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Affiliation(s)
- Mehran Rahimi
- Faculty of Medical Science, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, UK.,Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Mojtaba Daghighi
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Behiye Özcan
- Department of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Fareeba Sheedfar
- Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marzyeh Amini
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Tommaso Mazza
- Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Valerio Pazienza
- Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Mahdi M Motazacker
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
| | - Morteza Mahmoudi
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.,Department of Nanotechnology and Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Felix W M De Rooij
- Department of Cardiovascular Genetics, Metabolism, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Eric Sijbrands
- Department of Cardiovascular Genetics, Metabolism, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands
| | - Farhad Rezaee
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands.,Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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37
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Singh SK, Fiorelli R, Kupp R, Rajan S, Szeto E, Lo Cascio C, Maire CL, Sun Y, Alberta JA, Eschbacher JM, Ligon KL, Berens ME, Sanai N, Mehta S. Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway. Cell Rep 2016; 16:950-966. [PMID: 27396340 PMCID: PMC4963280 DOI: 10.1016/j.celrep.2016.06.045] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 04/28/2016] [Accepted: 06/09/2016] [Indexed: 12/31/2022] Open
Abstract
In glioblastoma, invasion and proliferation are presumed to be mutually exclusive events; however, the molecular mechanisms that mediate this switch at the cellular level remain elusive. Previously, we have shown that phospho-OLIG2, a central-nervous-system-specific transcription factor, is essential for tumor growth and proliferation. Here, we show that the modulation of OLIG2 phosphorylation can trigger a switch between proliferation and invasion. Glioma cells with unphosphorylated OLIG2(S10, S13, S14) are highly migratory and invasive, both in vitro and in vivo. Mechanistically, unphosphorylated OLIG2 induces TGF-β2 expression and promotes invasive mesenchymal properties in glioma cells. Inhibition of the TGF-β2 pathway blocks this OLIG2-dependent invasion. Furthermore, ectopic expression of phosphomimetic Olig2 is sufficient to block TGF-β2-mediated invasion and reduce expression of invasion genes (ZEB1 and CD44). Our results not only provide a mechanistic insight into how cells switch from proliferation to invasion but also offer therapeutic opportunities for inhibiting dissemination of gliomas.
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Affiliation(s)
- Shiv K Singh
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Roberto Fiorelli
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Robert Kupp
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Sindhu Rajan
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Emily Szeto
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Costanza Lo Cascio
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Cecile L Maire
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yu Sun
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - John A Alberta
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Jennifer M Eschbacher
- Division of Neuropathology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Keith L Ligon
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael E Berens
- Cancer and Cell Biology Division, Translational Genomics Institute, Phoenix, AZ 85004, USA
| | - Nader Sanai
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Shwetal Mehta
- Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
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38
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McLellan AS, Langlands K, Kealey T. Exhaustive identification of human class II basic helix-loop-helix proteins by virtual library screening. Mech Dev 2016; 119 Suppl 1:S285-91. [PMID: 14516699 DOI: 10.1016/s0925-4773(03)00130-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cellular proliferation, specification and differentiation in developing tissues are tightly coordinated by groups of transcription factors in response to extrinsic and intrinsic signals. Furthermore, renewable pools of stem cells in adult tissues are subject to similar regulation. Basic helix-loop-helix (bHLH) proteins are a group of transcription factors that exert such a determinative influence on a variety of developmental pathways from C. elegans to humans, and we wished to exclusively identify novel members from within the whole human bHLH family. We have, therefore, developed an 'empirical custom fingerprint', to define the class II bHLH domain and exclusively identify these proteins in silico. We have identified nine previously uncharacterised human class II proteins, four of which were novel, by interrogating conceptual translations of the GenBank HTGS database. RT-PCR and mammalian 2-hybrid analysis of a subset of the factors demonstrated that they were indeed expressed, and were able to interact with an appropriate binding partner in vitro. Thus, we are now approaching an almost complete listing of human class II bHLH factors.
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Affiliation(s)
- Andrew S McLellan
- Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, UK.
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39
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Applicable advances in the molecular pathology of glioblastoma. Brain Tumor Pathol 2015; 32:153-62. [PMID: 26078107 DOI: 10.1007/s10014-015-0224-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 06/01/2015] [Indexed: 12/21/2022]
Abstract
Comprising more than 80% of malignant brain tumors, glioma has proven to be a daunting cause of mortality in a vast majority of the human population. Progressive and extensive research on malignant glioma has substantially enhanced our understanding of glioma cell biology and molecular pathology. Subtypes of glioma such as astrocytoma and oligodendroglioma are currently grouped together into one pathological class, where they show many differences in histology and molecular etiology. This indicates that it may be beneficial to consider a new and radical subclassification. Thus, we summarize recent developments in glioblastoma multiforme (GBM) subtypes, immunohistochemical analyses useful for diagnoses and the biological evaluation and therapeutic implications of gliomas in this review.
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40
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Beyeler S, Joly S, Fries M, Obermair FJ, Burn F, Mehmood R, Tabatabai G, Raineteau O. Targeting the bHLH transcriptional networks by mutated E proteins in experimental glioma. Stem Cells 2015; 32:2583-95. [PMID: 24965159 DOI: 10.1002/stem.1776] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 05/06/2014] [Accepted: 05/19/2013] [Indexed: 01/15/2023]
Abstract
Glioblastomas (GB) are aggressive primary brain tumors. Helix-loop-helix (HLH, ID proteins) and basic HLH (bHLH, e.g., Olig2) proteins are transcription factors that regulate stem cell proliferation and differentiation throughout development and into adulthood. Their convergence on many oncogenic signaling pathways combined with the observation that their overexpression in GB correlates with poor clinical outcome identifies these transcription factors as promising therapeutic targets. Important dimerization partners of HLH/bHLH proteins are E proteins that are necessary for nuclear translocation and DNA binding. Here, we overexpressed a wild type or a dominant negative form of E47 (dnE47) that lacks its nuclear localization signal thus preventing nuclear translocation of bHLH proteins in long-term glioma cell lines and in glioma-initiating cell lines and analyzed the effects in vitro and in vivo. While overexpression of E47 was sufficient to induce apoptosis in absence of bHLH proteins, dnE47 was necessary to prevent nuclear translocation of Olig2 and to achieve similar proapoptotic responses. Transcriptional analyses revealed downregulation of the antiapoptotic gene BCL2L1 and the proproliferative gene CDC25A as underlying mechanisms. Overexpression of dnE47 in glioma-initiating cell lines with high HLH and bHLH protein levels reduced sphere formation capacities and expression levels of Nestin, BCL2L1, and CDC25A. Finally, the in vivo induction of dnE47 expression in established xenografts prolonged survival. In conclusion, our data introduce a novel approach to jointly neutralize HLH and bHLH transcriptional networks activities, and identify these transcription factors as potential targets in glioma.
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Affiliation(s)
- Sarah Beyeler
- Brain Research Institute, University of Zurich/Swiss Federal Institute of Technology Zurich, Zurich, Switzerland
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41
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Weider M, Wegener A, Schmitt C, Küspert M, Hillgärtner S, Bösl MR, Hermans-Borgmeyer I, Nait-Oumesmar B, Wegner M. Elevated in vivo levels of a single transcription factor directly convert satellite glia into oligodendrocyte-like cells. PLoS Genet 2015; 11:e1005008. [PMID: 25680202 PMCID: PMC4334169 DOI: 10.1371/journal.pgen.1005008] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/15/2015] [Indexed: 11/18/2022] Open
Abstract
Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies. Developmental or acquired defects of oligodendrocytes or their myelin sheaths impairs saltatory nerve conduction in the central nervous system and thus leads to severe neurological diseases. Strategies to regenerate or replace these cells require a deeper understanding of the regulatory processes that underlie their generation during development. Here we show in a Sox10 overexpressing mouse model that increase of the levels of a single transcription factor during embryogenesis efficiently converts the already Sox10 expressing satellite glial cells of the peripheral nervous system into oligodendrocyte-like cells by a mechanism that does not simply recapitulate developmental oligodendrogenesis but involves direct Sox10-dependent induction of the oligodendroglial differentiation network. Our study identifies mechanisms that may help to convert other cell types into oligodendrocytes and thus prove eventually useful for therapies of myelin diseases.
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Affiliation(s)
- Matthias Weider
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Amélie Wegener
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Schmitt
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Melanie Küspert
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Simone Hillgärtner
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael R. Bösl
- Experimentelle Biomedizin, Rudolf-Virchow-Zentrum, Universitätsklinikum Würzburg, Würzburg, Germany
| | | | - Brahim Nait-Oumesmar
- Institut du Cerveau et de la Moelle Epinière, ICM, Inserm U1127, Université Pierre et Marie Curie, Sorbonne Paris Cité, UMR-S1127, CNRS UMR 7225, Paris, France
| | - Michael Wegner
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- * E-mail:
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Abstract
The WHO grading scheme for glial neoplasms assigns Grade II to 5 distinct tumors of astrocytic or oligodendroglial lineage: diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, and pilomyxoid astrocytoma. Although commonly referred to collectively as among the "low-grade gliomas," these 5 tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because managing and predicting the course of these tumors has historically proven challenging, translational research regarding Grade II gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO Grade II gliomas remains nebulous. The authors' goal for this review was to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these 5 WHO Grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, they discuss the emerging evidence suggesting molecular differences between adult and pediatric Grade II gliomas. Finally, they present an overview of current strategies for using molecular data to classify low-grade gliomas into clinically relevant categories based on tumor biology.
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Affiliation(s)
- Nicholas F Marko
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
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43
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Zong H, Parada LF, Baker SJ. Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol 2015; 7:cshperspect.a020610. [PMID: 25635044 DOI: 10.1101/cshperspect.a020610] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Malignant glioma remains incurable despite tremendous advancement in basic research and clinical practice. The identification of the cell(s) of origin should provide deep insights into leverage points for one to halt disease progression. Here we summarize recent studies that support the notion that neural stem cell (NSC), astrocyte, and oligodendrocyte precursor cell (OPC) can all serve as the cell of origin. We also lay out important considerations on technical rigor for further exploring this subject. Finally, we share perspectives on how one could apply the knowledge of cell of origin to develop effective treatment methods. Although it will be a difficult battle, victory should be within reach as along as we continue to assimilate new information and facilitate the collaboration among basic scientists, translational researchers, and clinicians.
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Affiliation(s)
- Hui Zong
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908
| | - Luis F Parada
- Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Suzanne J Baker
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105
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44
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Trépant AL, Bouchart C, Rorive S, Sauvage S, Decaestecker C, Demetter P, Salmon I. Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms. Tumour Biol 2014; 36:1943-53. [PMID: 25384509 DOI: 10.1007/s13277-014-2800-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 11/03/2014] [Indexed: 12/15/2022] Open
Abstract
Despite advances in surgical and adjuvant treatments, overall survival of glioblastoma (GBM) patients remains poor. The cancer stem cell concept suggests that a rare stem cell population, called glioma stem cells (GSCs), has high ability to self-renewal leading to recurrence in GBM. The identification of specific markers of GSCs would provide a powerful tool to detect and to characterise them in order to develop targeted therapies. We carried out a comparative analysis based on the identification of inter-study concordances to identify the genes that exhibit at best differential levels of expression between GSC-enriched cell cultures and differentiated tumour cell cultures from independent studies using DNA chip microarray technologies. We finally studied the protein expression of the marker we considered the most specific by immunohistochemistry and semi-quantitative analysis on a retrospective series of 18 GBMs. Of the selected studies, 32 genes were retained. Among them, eight genes were identified to be overexpressed in GSC-enriched cultures compared to differentiated tumour cell cultures. Finally, among the eight genes, oligodendrocyte lineage transcription factor 2 (OLIG2) was characterised by the most different expression level in the "GSC model" compared to the "differentiated tumour cells model". Our approach suggests that OLIG2 is the most specific GSC marker; additional investigations with careful considerations about methodology and strategies of validation are, however, mandatory.
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Affiliation(s)
- Anne-Laure Trépant
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
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45
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Tan B, Yu J, Yin Y, Jia G, Jiang W, Yu L. The Olig family affects central nervous system development and disease. Neural Regen Res 2014; 9:329-36. [PMID: 25206819 PMCID: PMC4146145 DOI: 10.4103/1673-5374.128232] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2013] [Indexed: 11/04/2022] Open
Abstract
Neural cell differentiation and maturation is a critical step during central nervous system development. The oligodendrocyte transcription family (Olig family) is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system development and related diseases.
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Affiliation(s)
- Botao Tan
- Department of Rehabilitation Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jing Yu
- Department of Rehabilitation Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ying Yin
- Department of Rehabilitation Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Gongwei Jia
- Department of Rehabilitation Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wei Jiang
- Department of Rehabilitation Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Lehua Yu
- Department of Rehabilitation Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Smith KM, Maragnoli ME, Phull PM, Tran KM, Choubey L, Vaccarino FM. Fgfr1 inactivation in the mouse telencephalon results in impaired maturation of interneurons expressing parvalbumin. PLoS One 2014; 9:e103696. [PMID: 25116473 PMCID: PMC4130531 DOI: 10.1371/journal.pone.0103696] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 07/04/2014] [Indexed: 11/18/2022] Open
Abstract
Fibroblast growth factors (Fgfs) and their receptors (Fgfr) are expressed in the developing and adult CNS. Previous studies demonstrated a decrease in cortical interneurons and locomotor hyperactivity in mice with a conditional Fgfr1 deletion generated in radial glial cells during midneurogenesis (Fgfr1f/f;hGfapCre+). Here, we report earlier and more extensive inactivation of Fgfr1 in neuroepithelial cells of the CNS (Fgfr1f/f;NesCre+). Similar to findings in Fgfr1f/f;hGfapCre+ mice, parvalbumin positive (PV+) cortical interneurons are also decreased in the neocortex of Fgfr1f/f;NesCre+ mice when compared to control littermates (Fgfr1f/f). Fgfr1f/f;NesCre+ embryos do not differ from controls in the initial specification of GABAergic cells in the ganglionic eminence (GE) as assessed by in situ hybridization for Dlx2, Mash1 and Nkx2. Equal numbers of GABAergic neuron precursors genetically labeled with green fluorescent protein (GFP) were observed at P0 in Fgfr1f/f;hGfapCre+;Gad1-GFP mutant mice. However, fewer GFP+ and GFP+/PV+ interneurons were observed in these mutants at adulthood, indicating that a decrease in cortical interneuron markers is occurring postnatally. Fgfr1 is expressed in cortical astrocytes in the postnatal brain. To test whether the astrocytes of mice lacking Fgfr1 are less capable of supporting interneurons, we co-cultured wild type Gad1-GFP+ interneuron precursors isolated from the medial GE (MGE) with astrocytes from Fgfr1f/f control or Fgfr1f/f;hGfapCre+ mice. Interneurons grown on Fgfr1 deficient astrocytes had small soma size and fewer neurites per cell, but no differences in cell survival. Decreased soma size of Gad67 immunopositive interneurons was also observed in the cortex of adult Fgfr1f/f;NesCre+ mice. Our data indicate that astrocytes from Fgfr1 mutants are impaired in supporting the maturation of cortical GABAergic neurons in the postnatal period. This model may elucidate potential mechanisms of impaired PV interneuron maturation relevant to neuropsychiatric disorders that develop in childhood and adolescence.
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Affiliation(s)
- Karen Müller Smith
- Child Study Center, Yale University, New Haven, Connecticut, United States of America
| | | | - Pooja M. Phull
- Child Study Center, Yale University, New Haven, Connecticut, United States of America
| | - Kathy May Tran
- Child Study Center, Yale University, New Haven, Connecticut, United States of America
| | - Lisha Choubey
- Department of Biology, University of Louisiana at Lafayette, Lafayette, Louisiana, United States of America
| | - Flora M. Vaccarino
- Child Study Center, Yale University, New Haven, Connecticut, United States of America
- Department of Neurobiology, Yale University, New Haven, Connecticut, United States of America
- Kavli Institute for Neuroscience, Yale University, New Haven, Connecticut, United States of America
- * E-mail:
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An amino terminal phosphorylation motif regulates intranuclear compartmentalization of Olig2 in neural progenitor cells. J Neurosci 2014; 34:8507-18. [PMID: 24948806 DOI: 10.1523/jneurosci.0309-14.2014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The bHLH transcription factor Olig2 is expressed in cycling neural progenitor cells but also in terminally differentiated, myelinating oligodendrocytes. Sustained expression of Olig2 is counterintuitive because all known functions of the protein in expansion of neural progenitors and specification of oligodendrocyte progenitors are completed with the formation of mature white matter. How are the biological functions of Olig2 suppressed in terminally differentiated oligodendrocytes? In previous studies, we have shown that a triple serine motif in the amino terminus of Olig2 is phosphorylated in cycling neural progenitors but not in their differentiated progeny. We now show that phosphorylation of the triple serine motif regulates intranuclear compartmentalization of murine Olig2. Phosphorylated Olig2 is preferentially localized to a transcriptionally active "open" chromatin compartment together with coregulator proteins essential for regulation of gene expression. Unphosphorylated Olig2, as seen in mature white matter, is localized mainly within a transcriptionally inactive, chromatin fraction characterized by condensed and inaccessible DNA. Of special note is the observation that the p53 tumor suppressor protein is confined to the open chromatin fraction. Proximity ligation assays show that phosphorylation brings Olig2 within 30 nm of p53 within the open chromatin compartment. The data thus shed light on previously noted promitogenic functions of phosphorylated Olig2, which reflect, at least in part, an oppositional relationship with p53 functions.
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Olig2 labeling index is correlated with histological and molecular classifications in low-grade diffuse gliomas. J Neurooncol 2014; 120:283-91. [PMID: 25085214 DOI: 10.1007/s11060-014-1568-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 07/22/2014] [Indexed: 01/22/2023]
Abstract
Diagnosis of low-grade diffuse gliomas based on morphology is highly subjective and, therefore, is often difficult, with significant intra- and interobserver variability. Here, we investigated WHO grade II diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas for immunohistochemical expression of Olig2, measuring its labeling index (LI), and evaluated the significance of Olig2 LI in the histological and molecular classifications. The means of Olig2 LI in glioma cells were 43.7 % in diffuse astrocytomas, 59.3 % in oligoastrocytomas and 76.1 % in oligodendrogliomas. There was a statistically significant difference between all pairs of histological types. The mean of Olig2 LI of gliomas with 1p/19q loss ± IDH1/2 mutation, the majority of them being oligodendrogliomas, was significantly higher than the means of those with TP53 mutation ± IDH1/2 mutation and IDH1/2 mutation only, the majority of which were diffuse astrocytomas (70.1 vs. 47.2 and 46.5 %, respectively). When categorized according to the classification of Jiao et al., Olig2 LI of I-CF gliomas (cases with IDH and one or more of CIC, FUBP1 or combined 1p/19q loss; mean 71.0 %) was significantly higher than that of I-A gliomas (cases with IDH and ATRX alterations; mean 45.3 %). These molecular classifications were reported to correlate well with clinical outcome. However, borderlines of Olig2 LI were broad and could not clearly distinguish genotypes in the molecular classifications. In conclusion, Olig2 LI cannot be taken as a complete surrogate marker for molecular genotype, but could possibly provide some ancillary information when molecular assay is not availabe.
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Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O, Hawkins C, Majewski J, Jones C, Costello JF, Iavarone A, Aldape K, Brennan CW, Jabado N, Pfister SM. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 2014; 14:92-107. [PMID: 24457416 PMCID: PMC4003223 DOI: 10.1038/nrc3655] [Citation(s) in RCA: 421] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and provided deeper insights into gliomagenesis across all age groups, which has highlighted key distinctions but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.
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Affiliation(s)
- Dominik Sturm
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany
| | - Sebastian Bender
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany
| | - David T.W. Jones
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
| | - Peter Lichter
- Division of Molecular Genetics, German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
| | - Jacques Grill
- Brain Tumor Program, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Universite Paris Sud, 114 Rue Eduoard Vaillant, 94805 Villejuif, France
| | - Oren Becher
- Division of Pediatric Hematology/Oncology, Duke University Medical Center, DUMC 91001, Durham, NC 27710, USA
| | - Cynthia Hawkins
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada
| | - Jacek Majewski
- Division of Experimental Medicine and Department of Human Genetics, McGill University and McGill University Health Centre, 2155 Guy Street, Montreal, QC, H3H 2R9, Canada
| | - Chris Jones
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
| | - Joseph F. Costello
- Brain Tumor Research Center, Department of Neurosurgery, University of California, 2340 Sutter St., San Francisco, CA 94143, USA
| | - Antonio Iavarone
- Institute for Cancer Genetics and Departments of Pathology and Neurology, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA
| | - Kenneth Aldape
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0085, Houston, TX 77030, USA
| | - Cameron W. Brennan
- Human Oncology & Pathogenesis Program and Department of Neurosurgery, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
| | - Nada Jabado
- Division of Experimental Medicine and Department of Human Genetics, McGill University and McGill University Health Centre, 2155 Guy Street, Montreal, QC, H3H 2R9, Canada
| | - Stefan M. Pfister
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany
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50
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p53 in neurodegenerative diseases and brain cancers. Pharmacol Ther 2013; 142:99-113. [PMID: 24287312 DOI: 10.1016/j.pharmthera.2013.11.009] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 11/07/2013] [Indexed: 12/21/2022]
Abstract
More than thirty years elapsed since a protein, not yet called p53 at the time, was detected to bind SV40 during viral infection. Thousands of papers later, p53 evolved as the main tumor suppressor involved in growth arrest and apoptosis. A lot has been done but the protein has not yet revealed all its secrets. Particularly important is the observation that in totally distinct pathologies where apoptosis is either exacerbated or impaired, p53 appears to play a central role. This is exemplified for Alzheimer's and Parkinson's diseases that represent the two main causes of age-related neurodegenerative affections, where cell death enhancement appears as one of the main etiological paradigms. Conversely, in cancers, about half of the cases are linked to mutations in p53 leading to the impairment of p53-dependent apoptosis. The involvement of p53 in these pathologies has driven a huge amount of studies aimed at designing chemical tools or biological approaches to rescue p53 defects or over-activity. Here, we describe the data linking p53 to neurodegenerative diseases and brain cancers, and we document the various strategies to interfere with p53 dysfunctions in these disorders.
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