Review of Current Human Genome-Scale Metabolic Models for Brain Cancer and Neurodegenerative Diseases.

Brain disorders represent 32% of the global disease burden, with 169 million Europeans affected. Constraint-based metabolic modelling and other approaches have been applied to predict new treatments for these and other diseases. Many recent studies focused on enhancing, among others, drug predictions by generating generic metabolic models of brain cells and on the contextualisation of the genome-scale metabolic models with expression data. Experimental flux rates were primarily used to constrain or validate the model inputs. Bi-cellular models were reconstructed to study the interaction between different cell types. This review highlights the evolution of genome-scale models for neurodegenerative diseases and glioma. We discuss the advantages and drawbacks of each approach and propose improvements, such as building bi-cellular models, tailoring the biomass formulations for glioma and refinement of the cerebrospinal fluid composition

Interfering with long non-coding RNA MIR22HG processing inhibits glioblastoma progression through suppression of Wnt/β-catenin signalling

Long non-coding RNAs play critical roles in tumour progression. Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long non-coding RNAs in glioblastoma. The main purpose of this work was to determine the impact of MIR22HG on glioblastoma growth and invasion and to elucidate its mechanistic function. The MIR22HG/miR-22 axis was highly expressed in glioblastoma as well as in glioma stem-like cells compared to normal neural stem cells. In glioblastoma, increased expression of MIR22HG is associated with poor prognosis. Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/β-catenin signalling pathway through loss of miR-22-3p and -5p. This leads to attenuated cell proliferation, invasion and in vivo tumour growth. We further show that two genes, SFRP2 and PCDH15, are direct targets of miR-22-3p and -5p and inhibit Wnt signalling in glioblastoma. Finally, based on the 3D structure of the pre-miR-22, we identified a specific small-molecule inhibitor, AC1L6JTK, that inhibits the enzyme Dicer to block processing of pre-miR-22 into mature miR-22. AC1L6JTK treatment caused an inhibition of tumour growth in vivo. Our findings show that MIR22HG is a critical inducer of the Wnt/β-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.publishedVersio

XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase

Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy.publishedVersio

Altered metabolic landscape in IDH‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Heterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors

Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.publishedVersio

Implications des histones deacetylases de I et II dans la réponse au stress

En réponse à des stress environnementaux, la cellule met en place une réponse rapide et transitoire visant à assurer sa survie. Cette réponse se traduit par l'activation du facteur HSF1(Heat shock factor 1) qui induit l'expression des gènes codant pour des protéines de choc thermique (ou HSP). L'activation des gènes hsp s'accompagne de la répression de la plupart des autres gènes cellulaires. Si l'on connait assez bien aujourd'hui les mécanismes associés à l'activation des gènes de choc thermique, peu de données existent concernant les mécanismes mis en jeu dans l'inactivation globale. Nous avons engagé un travail visant à caractériser les modifications épigénétiques qui accompagnent cette répression, ainsi qu'à identifier les acteurs impliqués. Par des approches moléculaires et in situ nous avons montré que les HDACs (Histones Décaétylases) sont de nouveaux régulateurs de la réponse au stress. Le stress thermique induit une régulation fine de l'épigénome, notamment une déacétylation globale des histones de cœur, médiée par des HDACS de classe l, HDAC1 et 2. Au niveau du cytoplasme, les HDACs régulent également la réponse au stress. En effet, lors d'un stress protéotoxique, nous avons montré qu'HDAC6 joue un rôle indispensable dans l'initiation de cette réponse, en dissociant le facteur HSFl de ses régulateurs négatifs. En conséquence, HDAC6 joue un rôle dans l'induction des protéines HSPs en réponse à ce stress de type agrégats. En conclusion, en identifiant les HDACs comme de nouveaux facteurs de la réponse au stress, nos travaux permettent de mettre en lien entre deux cibles faisant l'objet de nombreux travaux en cancérologie: HSPs et HDACs.ln response to environmental stress (heat shock, hypoxia, heavy metals exposure), cells have developed rapid and transitory mechanisms to protect themselves from the stress-induced damages. This stress response is characterized by the activation of HSF1 (Heat Shock Factor1), a key factor involved in the induction of the HSP (Heat Shock Proteins) encoded genes. ln contrast toheat shock genes induction, most of the genome is repressed du ring stress. If the mechanisms involved in the activation of HSP genes have been investigated in details, less is known about the global repression of the genome. We started to investigate the epigenetic mechanisms that underline this genome repression and identify the molecular basis of this phenomenon. By molecular and in situ approaches, we showed that HDACs (Histone Deacetylases) are new regulators of stress response. Heat shock induces major epigenetic changes, specially a global deacetylation of core histones. We showed that class 1 HDAC, HDACl and HDAC2 mediates the heat-induced deacetylation. This event is regulated by HSF1, probably through its interaction with HDACl and HDAC2. ln the cytoplasm, HDACS are also able to regulate stress response. Indeed, upon proteotoxic stress for example, proteasome inhibition, we showed that HDAC6 play a critical role in initiating the stress response. It mediates the dissociation of HSFl from its repressor complex and HDAC6 has an impact in HSP induction in response to stress. ln conclusion, we identify HDACs as new important factors of stress response. Thanks to this work, we have linked two classes of proteins that are targeted by anti-cancer therapy: HSPs and HDACs.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Dual blockade of STAT3 and EGFR: a key to unlock drug resistance in glioblastoma?

peer reviewe

Databases for lncRNAs: a comparative evaluation of emerging tools.

peer reviewedThe vast majority of the human transcriptome does not code for proteins. Advances in transcriptome arrays and deep sequencing are giving rise to a fast accumulation of large data sets, particularly of long noncoding RNAs (lncRNAs). Although it is clear that individual lncRNAs may play important and diverse biological roles, there is a large gap between the number of existing lncRNAs and their known relation to molecular/cellular function. This and related information have recently been gathered in several databases dedicated to lncRNA research. Here, we review the content of general and more specialized databases on lncRNAs. We evaluate these resources in terms of the quality of annotations, the reporting of validated or predicted molecular associations, and their integration with other resources and computational analysis tools. We illustrate our findings using known and novel cancer-related lncRNAs. Finally, we discuss limitations and highlight potential future directions for these databases to help delineating functions associated with lncRNAs

Altered metabolic landscape in IDH-mutant gliomasaffects phospholipid, energy, and oxidative stress pathways

Contains fulltext : 180458.pdf (publisher's version ) (Open Access

Impact of IDH Mutations, the 1p/19q Co-Deletion and the G-CIMP Status on Alternative Splicing in Diffuse Gliomas

By generating protein diversity, alternative splicing provides an important oncogenic pathway. Isocitrate dehydrogenase (IDH) 1 and 2 mutations and 1p/19q co-deletion have become crucial for the novel molecular classification of diffuse gliomas, which also incorporates DNA methylation profiling. In this study, we have carried out a bioinformatics analysis to examine the impact of the IDH mutation, as well as the 1p/19q co-deletion and the glioma CpG island methylator phenotype (G-CIMP) status on alternative splicing in a cohort of 662 diffuse gliomas from The Cancer Genome Atlas (TCGA). We identify the biological processes and molecular functions affected by alternative splicing in the various glioma subgroups and provide evidence supporting the important contribution of alternative splicing in modulating epigenetic regulation in diffuse gliomas. Targeting the genes and pathways affected by alternative splicing might provide novel therapeutic opportunities against gliomas