scholarly journals Stem cell signature in glioblastoma: therapeutic development for a moving target

2015 ◽  
Vol 122 (2) ◽  
pp. 324-330 ◽  
Author(s):  
Ichiro Nakano
Keyword(s):  
High Grade Glioma ◽  
Core Gene ◽  
Metabolic Reprogramming ◽  
Molecular Signature ◽  
Transcriptional Analysis ◽  
Clinical Implications ◽  
Pathways Analysis ◽  
Therapeutic Development

Tumor heterogeneity of adult high-grade glioma (HGG) is recognized in 3 major subtypes based on core gene signatures. However, the molecular signatures and clinical implications of glioma stem cells (GSCs) in individual HGG subtypes remain poorly characterized. Recently genome-wide transcriptional analysis identified two mutually exclusive GSC subtypes with distinct dysregulated signaling and metabolic pathways. Analysis of genetic profiles and phenotypic assays distinguished proneural (PN) from mesenchymal (MES) GSCs and revealed a striking correlation with the corresponding PN or MES HGGs. Similar to HGGs with a MES signature, MES GSCs display more aggressive phenotypes both in vitro and in vivo. Furthermore, MES GSCs are markedly resistant to radiation as compared with PN GSCs, consistent with the relative radiation resistance of MES GBM compared with other subtypes. A systems biology approach has identified a set of transcription factors as the master regulators for the MES signature. Metabolic reprogramming in MES GSCs has also been noticed with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes. This review summarizes recent progress in the characterization of the molecular signature in distinct HGG and GSC subtypes and plasticity between different GSC subtypes as well as between GSCs and non-GSCs in HGG tumors. Clinical implications of the translational GSC research are also discussed.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

scholarly journals Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer K. Dowling ◽  
Remsha Afzal ◽  
Linden J. Gearing ◽  
Mariana P. Cervantes-Silva ◽  
Stephanie Annett ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Mitochondrial Dynamics ◽  
Interleukin 10 ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Macrophage Polarisation ◽  
Inflammatory Status ◽  
Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

scholarly journals Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Laetitia Seguin ◽  
Soline Odouard ◽  
Francesca Corlazzoli ◽  
Sarah Al Haddad ◽  
Laurine Moindrot ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Survival ◽  
Small Gtpases ◽  
Molecular Signature ◽  
Carbohydrate Binding ◽  
Pancreatic Cancers ◽  
Galectin 3 ◽  
Pharmacologic Inhibition

AbstractRecently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glioblastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3-mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and β1 integrin, which are both required for macropinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of-principle for innovative therapeutic strategies to exploit this Achilles’ heel for a significant and unique subset of GBM patients.

scholarly journals Localization matters: nuclear-trapped Survivin sensitizes glioblastoma cells to temozolomide by elevating cellular senescence and impairing homologous recombination

2021 ◽  
Author(s):  
Thomas R. Reich ◽  
Christian Schwarzenbach ◽  
Juliana Brandstetter Vilar ◽  
Sven Unger ◽  
Fabian Mühlhäusler ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Nuclear Export ◽  
Cell Model ◽  
Chromosome Instability ◽  
Direct Interaction ◽  
High Grade Glioma ◽  
Strand Break ◽  
Γh2ax Foci

AbstractTo clarify whether differential compartmentalization of Survivin impacts temozolomide (TMZ)-triggered end points, we established a well-defined glioblastoma cell model in vitro (LN229 and A172) and in vivo, distinguishing between its nuclear and cytoplasmic localization. Expression of nuclear export sequence (NES)-mutated Survivin (SurvNESmut-GFP) led to impaired colony formation upon TMZ. This was not due to enhanced cell death but rather due to increased senescence. Nuclear-trapped Survivin reduced homologous recombination (HR)-mediated double-strand break (DSB) repair, as evaluated by γH2AX foci formation and qPCR-based HR assay leading to pronounced induction of chromosome aberrations. Opposite, clones, expressing free-shuttling cytoplasmic but not nuclear-trapped Survivin, could repair TMZ-induced DSBs and evaded senescence. Mass spectrometry-based interactomics revealed, however, no direct interaction of Survivin with any of the repair factors. The improved TMZ-triggered HR activity in Surv-GFP was associated with enhanced mRNA and stabilized RAD51 protein expression, opposite to diminished RAD51 expression in SurvNESmut cells. Notably, cytoplasmic Survivin could significantly compensate for the viability under RAD51 knockdown. Differential Survivin localization also resulted in distinctive TMZ-triggered transcriptional pathways, associated with senescence and chromosome instability as shown by global transcriptome analysis. Orthotopic LN229 xenografts, expressing SurvNESmut exhibited diminished growth and increased DNA damage upon TMZ, as manifested by PCNA and γH2AX foci expression, respectively, in brain tissue sections. Consequently, those mice lived longer. Although tumors of high-grade glioma patients expressed majorly nuclear Survivin, they exhibited rarely NES mutations which did not correlate with survival. Based on our in vitro and xenograft data, Survivin nuclear trapping would facilitate glioma response to TMZ.

scholarly journals TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Jenna Minami ◽  
Nicholas Bayley ◽  
Christopher Tse ◽  
Henan Zhu ◽  
Danielle Morrow ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cultured Cells ◽  
Tumor Biology ◽  
Metabolic Reprogramming ◽  
Neoplastic Progression ◽  
Extracellular Milieu ◽  
Metabolic Defects ◽  
Metabolic Heterogeneity

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.

scholarly journals Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Xiaoxiong Wang ◽  
Heping Wang ◽  
Jiajun Xu ◽  
Xu Hou ◽  
Haoqiang Zhan ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Malignant Tumors ◽  
Disease Free Survival ◽  
High Grade Glioma ◽  
Poor Overall Survival ◽  
Survival Prognosis ◽  
Who Grade ◽  
And Migration

AbstractHigh-grade glioma is the most common and aggressive primary brain tumor in adults with poor therapeutic efficiency and survival prognosis. Cell division cycle associated 8 (CDCA8) has been well known as a cell cycle regulator and tumor promotor in various malignant tumors. However, its biological role in glioma still remains unclear. Our results showed that high level of CDCA8 was significantly correlated with advanced WHO grade and poor overall survival and disease-free survival prognosis. In vitro and in vivo investigations demonstrated that CDCA8 promoted the glioma malignancy by promoting cell proliferation, cell migration, and inhibiting cell apoptosis. Moreover, we found its synergetic biological protein—E2F1 by the gene microarray chip. In this study, we revealed that CDCA8 synergized with E2F1 facilitated the proliferation and migration of glioma. In conclusion, our study provides a novel promising therapeutic targets and prognostic biomarkers for malignant glioma treatment.

scholarly journals NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by apatinib

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Zheng Chen ◽  
Xiangyu Wei ◽  
Xueyi Wang ◽  
Xuan Zheng ◽  
Bowen Chang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Hypoxia Inducible Factor ◽  
Mitochondrial Respiratory Chain ◽  
Metabolic Reprogramming ◽  
Tumor Cell Apoptosis ◽  
Survival Gene ◽  
A Subunit ◽  
Tumor Types

AbstractNADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a subunit of Complex I of the mitochondrial respiratory chain, which is important in metabolic reprogramming and oxidative stress in multiple cancers. However, the biological role and molecular regulation of NDUFA4L2 in glioblastoma (GBM) are poorly understood. Here, we found that NDUFA4L2 was significantly upregulated in GBM; the elevated levels were correlated with reduced patient survival. Gene knockdown of NDUFA4L2 inhibited tumor cell proliferation and enhanced apoptosis, while tumor cells initiated protective mitophagy in vitro and in vivo. We used lentivirus to reduce expression levels of NDUFA4L2 protein in GBM cells exposed to mitophagy blockers, which led to a significant enhancement of tumor cell apoptosis in vitro and inhibited the development of xenografted tumors in vivo. In contrast to other tumor types, NDUFA4L2 expression in GBM may not be directly regulated by hypoxia-inducible factor (HIF)-1α, because HIF-1α inhibitors failed to inhibit NDUFA4L2 in GBM. Apatinib was able to effectively target NDUFA4L2 in GBM, presenting an alternative to the use of lentiviruses, which currently cannot be used in humans. Taken together, our data suggest the use of NDUFA4L2 as a potential therapeutic target in GBM and demonstrate a practical treatment approach.

scholarly journals Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Hanyue Chang ◽  
Qiaoshi Xu ◽  
Jiayi Li ◽  
Mingyu Li ◽  
Zhiyuan Zhang ◽  
...  
Keyword(s):  
Critical Role ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Histone Deacetylase 3 ◽  
Proliferation And Metastasis ◽  
Immunosuppressive Microenvironment ◽  
Transcriptional Complex

AbstractPyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.

scholarly journals Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

2011 ◽  
Vol 80 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Chen Li ◽  
Kurniyati ◽  
Bo Hu ◽  
Jiang Bian ◽  
Jianlan Sun ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Biofilm Formation ◽  
Adult Population ◽  
Transcriptional Analysis ◽  
Wild Type ◽  
Content Type ◽  
Multiple Organs ◽  
Biochemical Analyses

ABSTRACTThe oral bacteriumPorphyromonas gingivalisis a key etiological agent of human periodontitis, a prevalent chronic disease that affects up to 80% of the adult population worldwide.P. gingivalisexhibits neuraminidase activity. However, the enzyme responsible for this activity, its biochemical features, and its role in the physiology and virulence ofP. gingivalisremain elusive. In this report, we found thatP. gingivalisencodes a neuraminidase, PG0352 (SiaPg). Transcriptional analysis showed thatPG0352is monocistronic and is regulated by a sigma70-like promoter. Biochemical analyses demonstrated that SiaPgis an exo-α-neuraminidase that cleaves glycosidic-linked sialic acids. Cryoelectron microscopy and tomography analyses revealed that thePG0352deletion mutant (ΔPG352) failed to produce an intact capsule layer. Compared to the wild type,in vitrostudies showed that ΔPG352 formed less biofilm and was less resistant to killing by the host complement.In vivostudies showed that while the wild type caused a spreading type of infection that affected multiple organs and all infected mice were killed, ΔPG352 only caused localized infection and all animals survived. Taken together, these results demonstrate that SiaPgis an important virulence factor that contributes to the biofilm formation, capsule biosynthesis, and pathogenicity ofP. gingivalis, and it can potentially serve as a new target for developing therapeutic agents againstP. gingivalisinfection.

scholarly journals Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

2021 ◽  
Vol 22 (11) ◽  
pp. 5602
Author(s):  
Hyeon Young Park ◽  
Mi-Jin Kim ◽  
Seunghyeong Lee ◽  
Jonghwa Jin ◽  
Sungwoo Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Metabolic Reprogramming ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
And Migration ◽  
Proliferation And Migration

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

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