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Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (HAdV-C5) has been the most utilised clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to HAdV-C5 coupled with the infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an HAdV-C5-based platform using the fibre knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptor coxsackie, adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at a low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance the specificity of transgene expression to GBM, we assessed the potential for tumour-specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tight GBM-specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour-specific promoter approaches may enable the development of efficacious therapies better suited to GBM. [ABSTRACT FROM AUTHOR]

Quantitative hyperspectral coherent Raman scattering microscopy merges imaging with spectroscopy and utilises quantitative data analysis algorithms to extract physically meaningful chemical components, spectrally and spatially-resolved, with sub-cellular resolution. This label-free non-invasive method has the potential to significantly advance our understanding of the complexity of living multicellular systems. Here, we have applied an in-house developed hyperspectral coherent anti-Stokes Raman scattering (CARS) microscope, combined with a quantitative data analysis pipeline, to imaging living mouse liver organoids as well as fixed mouse brain tissue sections xenografted with glioblastoma cells. We show that the method is capable of discriminating different cellular sub-populations, on the basis of their chemical content which is obtained from an unsupervised analysis, i.e. without prior knowledge. Specifically, in the organoids, we identify sub-populations of cells at different phases in the cell cycle, while in the brain tissue, we distinguish normal tissue from cancer cells, and, notably, tumours derived from transplanted cancer stem cells versus non-stem glioblastoma cells. The ability of the method to identify different sub-populations was validated by correlative fluorescence microscopy using fluorescent protein markers. These examples expand the application portfolio of quantitative chemical imaging by hyperspectral CARS microscopy to multicellular systems of significant biomedical relevance, pointing the way to new opportunities in non-invasive disease diagnostics. [ABSTRACT FROM AUTHOR]

The metabolic complexity and flexibility commonly observed in brain tumors, especially glioblastoma, is fundamental for their development and progression. The ability of tumor cells to modify their genetic landscape and adapt metabolically, subverts therapeutic efficacy, and inevitably instigates therapeutic resistance. To overcome these challenges and develop effective therapeutic strategies targeting essential metabolic processes, it is necessary to identify the mechanisms underlying heterogeneity and define metabolic preferences and liabilities of malignant cells. In this review, we will discuss metabolic diversity in brain cancer and highlight the role of cancer stem cells in regulating metabolic heterogeneity. We will also highlight potential therapeutic modalities targeting metabolic vulnerabilities and examine how intercellular metabolic signaling can shape the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered "undruggable" ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma. [ABSTRACT FROM AUTHOR]

Identification of targetable mechanisms that maintain glioblastoma cancer stem cells (CSCs) remain a priority. Our study reveals a new mechanism by which a disintegrin and metalloproteinase domain-like protein decysin 1 promotes CSC maintenance through the activation of a fibroblast growth factor autocrine signaling loop, which can be blocked pharmacologically. [ABSTRACT FROM AUTHOR]

Diffuse spread through brain parenchyma and the presence of hypoxic foci rimmed by neoplastic cells are two cardinal features of glioblastoma, and low oxygen is thought to drive movement of malignant gliomas in the core of the lesions. Transcription factors associated with epithelial-to-mesenchymal transition ( EMT) have been linked to this invasion, and we found that hypoxia increased in vitro invasion up to fourfold in glioblastoma neurosphere lines and induced the expression of ZEB1. Immunohistochemical assessment of 295 surgical specimens consisting of various types of pediatric and adult brain cancers showed that ZEB1 expression was significantly higher in infiltrative lesions than less invasive tumors such as pilocytic astrocytoma and ependymoma. ZEB1 protein was also present in human fetal periventricular stem and progenitor cells and ZEB1 inhibition impaired migration of in vitro propagated human neural stem cells. The induction of ZEB1 protein in hypoxic glioblastoma neurospheres could be partially blocked by the HIF1alpha inhibitor digoxin. Targeting ZEB1 blocked hypoxia-augmented invasion of glioblastoma cells in addition to slowing them in normoxia. These data support the role for ZEB1 in invasive and high-grade brain tumors and suggest its key role in promoting invasion in the hypoxic tumor core as well as in the periphery. [ABSTRACT FROM AUTHOR]

Adult neural stem cells (aNSCs) are the source for the continuous production of new neurons throughout life. This so-called adult neurogenesis has been extensively studied; the intermediate cellular stages are well documented. Recent discoveries have raised new controversies in the field, such as the notion that progenitor cells hold similar self-renewal potential as stem cells, or whether different types of aNSCs exist. Here, we discuss evidence for heterogeneity of aNSCs, including short-term and long-term self-renewing aNSCs, regional and temporal differences in aNSC function, and single cell transcriptomics. Reviewing various genetic mouse models used for targeting aNSCs and lineage tracing, we consider potential lineage relationships between Ascl1-, Gli1-, and Nestin-targeted aNSCs. We present a multidimensional model of adult neurogenesis that incorporates recent findings and conclude that stemness is a phenotype, a state of properties that can change with time, rather than a cell property, which is static and immutable. We argue that singular aNSCs do not exist. [ABSTRACT FROM AUTHOR]

Objective: Deep brain stimulation (DBS) has been used for more than a decade to treat Parkinson's disease (PD); however, its mechanism of action remains unknown. Given the close proximity of the electrode trajectory to areas of the brain known as the “germinal niches,” we sought to explore the possibility that DBS influences neural stem cell proliferation locally, as well as more distantly. Methods: We studied the brains of a total of 12 idiopathic Parkinson's disease patients that were treated with DBS (the electrode placement occurred 0.5–6 years before death), and who subsequently died of unrelated illnesses. These were compared to the brains of 10 control individuals without CNS disease, and those of 5 PD patients with no DBS. Results: Immunohistochemical analyses of the subventricular zone (SVZ) of the lateral ventricles, the third ventricle lining, and the tissue surrounding the DBS lead revealed significantly greater numbers of proliferating cells expressing markers of the cell cycle, plasticity, and neural precursor cells in PD-DBS tissue compared with both normal brain tissue and tissue from PD patients not treated with DBS. The level of cell proliferation in the SVZ in PD-DBS brains was 2–6 fold greater than that in normal and untreated PD brains. Conclusions: Our data suggest that DBS is capable of increasing cellular plasticity in the brain, and we hypothesize that it may have more widespread effects beyond the electrode location. It is unclear whether these effects of DBS have any symptomatic or other beneficial influences on PD. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant adult brain tumor and carries a poor prognosis due to primary and acquired resistance. While many cellular features of GBM have been documented, it is unclear if cells within these tumors extend a primary cilium, an organelle whose associated signaling pathways may regulate proliferation, migration, and survival of neural precursor and tumor cells. Using immunohistochemical and electron microscopy (EM) techniques, we screened human GBM tumor biopsies and primary cell lines for cilia. Immunocytochemical staining of five primary GBM cell lines revealed that between 8 and 25 % of the cells in each line possessed gamma tubulin-positive basal bodies from which extended acetylated, alpha-tubulin-positive axonemes. EM analyses confirmed the presence of cilia at the cell surface and revealed that their axonemes contained organized networks of microtubules, a structural feature consistent with our detection of IFT88 and Arl13b, two trafficked cilia proteins, along the lengths of the axonemes. Notably, cilia were detected in each of 23 tumor biopsies (22 primary and 1 recurrent) examined. These cilia were distributed across the tumor landscape including regions proximal to the vasculature and within necrotic areas. Moreover, ciliated cells within these tumors co-stained with Ki67, a marker for actively dividing cells, and ZEB1, a transcription factor that is upregulated in GBM and linked to tumor initiation, invasion, and chemoresistance. Collectively, our data show that subpopulations of cells within human GBM tumors are ciliated. In view of mounting evidence supporting roles of primary cilia in tumor initiation and propagation, it is likely that further study of the effects of cilia on GBM tumor cell function will improve our understanding of GBM pathogenesis and may provide new directions for GBM treatment strategies. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies-invasion and noninvasion-is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of noninvasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic capsule can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the leukocyte common antigen-related phosphatase receptor (PTPRF) as a putative intermediary between extracellular glycosylated CSPGs and noninvasive tumor cells. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion. [ABSTRACT FROM AUTHOR]

Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors. [ABSTRACT FROM AUTHOR]

It is commonly accepted that adult neurogenesis and gliogenesis follow the same principles through the mammalian class. However, it has been reported that neurogenesis might differ between species, even from the same order, like in rodents. Currently, it is not known if neural stem/progenitor cells (NSPCs) from various species differ in their cell identity and potential. NSPCs can be expanded ex vivo as neurospheres (NSph), a model widely used to study neurogenesis in vitro. Here we demonstrate that rat (r) and mouse (m) NSph display different cell identities, differentiation fate, electrophysiological function and tumorigenic potential. Adult rNSph consist mainly of oligodendroglial progenitors (OPCs), which after repeated passaging proliferate independent of mitogens, whereas adult mNSph show astroglial precursor-like characteristics and retain their mitogen dependency. Most of the cells in rNSph express OPC markers and spontaneously differentiate into oligodendrocytes after growth factor withdrawal. Electrophysiological analysis confirmed OPC characteristics. mNSph have different electrophysiological properties, they express astrocyte precursor markers and spontaneously differentiate primarily into astrocytes. Furthermore, rNSph have the potential to differentiate into oligodendrocytes and astrocytes, whereas mNSph are restricted to the astrocytic lineage. The phenotypic differences between rNSph and mNSph were not due to a distinct response to species specific derived growth factors and are probably not caused by autocrine mechanisms. Our findings suggest that NSph derived from adult rat and mouse brains display different cell identities. Thus, results urge for caution when data derived from NSph are extrapolated to other species or to the in vivo situation, especially when aimed towards the clinical use of human NSph. [ABSTRACT FROM AUTHOR]

Individual tumour cells display diverse functional behaviours in terms of proliferation rate, cell–cell interactions, metastatic potential and sensitivity to therapy. Moreover, sequencing studies have demonstrated surprising levels of genetic diversity between individual patient tumours of the same type. Tumour heterogeneity presents a significant therapeutic challenge as diverse cell types within a tumour can respond differently to therapies, and inter-patient heterogeneity may prevent the development of general treatments for cancer. One strategy that may help overcome tumour heterogeneity is the identification of tumour sub-populations that drive specific disease pathologies for the development of therapies targeting these clinically relevant sub-populations. Here, we have identified a dye-retaining brain tumour population that displays all the hallmarks of a tumour-initiating sub-population. Using a limiting dilution transplantation assay in immunocompromised mice, label-retaining brain tumour cells display elevated tumour-initiation properties relative to the bulk population. Importantly, tumours generated from these label-retaining cells exhibit all the pathological features of the primary disease. Together, these findings confirm dye-retaining brain tumour cells exhibit tumour-initiation ability and are therefore viable targets for the development of therapeutics targeting this sub-population. [ABSTRACT FROM AUTHOR]

The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 ± 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 ± 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient’s regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R2adjusted = 0.635), as well as the same patient’s ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R2adjusted = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain. [ABSTRACT FROM PUBLISHER]

Recent studies have found that cellular self-renewal capacity in brain cancer is heterogeneous, with only stem-like cells having this property. A link between adult stem cells and cancer stem cells remains, however, to be shown. Here, we describe the emergence of cancer stem-like cells from in vitro cultured brain stem cells. Adult rat subventricular zone (SVZ) stem cells transformed into tumorigenic cell lines after expansion in vitro. These cell lines maintained characteristic features of stem-like cells expressing Nestin, Musashi-1 and CD133, but continued to proliferate upon differentiation induction. Karyotyping detected multiple acquired chromosomal aberrations, and syngeneic transplantation into the brain of adult rats resulted in malignant tumor formation. Tumors revealed streak necrosis and displayed a neural as well as an undifferentiated phenotype. Deficient downregulation of platelet-derived growth factor (PDGF) receptor alpha was identified as candidate mechanism for tumor cell proliferation, and its knockdown by siRNA resulted in a reduction of cell growth. Our data point to adult brain precursor cells to be transformed in malignancies. Furthermore, in vitro expansion of adult neural stem cells, which will be mandatory for therapeutic strategies in neurological disorders, also harbors the risk for amplifying precursor cells with acquired genetic abnormalities and induction of malignant tumors after transplantation. [ABSTRACT FROM AUTHOR]

We have previously shown that soluble factors derived from mesenchymal stem cells (MSCs) induce oligodendrogenic fate and differentiation in adult rat neural progenitors (NPCs) in vitro. Here, we investigated if this pro-oligodendrogenic effect is maintained after cells have been transplanted onto rat hippocampal slice cultures, a CNS-organotypic environment. We first tested whether NPCs, that were pre-differentiated in vitro by MSC-derived conditioned medium, would generate oligodendrocytes after transplantation. This approach resulted in the loss of grafted NPCs, suggesting that oligodendroglial pre-differentiated cells could not integrate in the tissue and therefore did not survive grafting. However, when NPCs together with MSCs were transplanted in situ into hippocampal slice cultures, the grafted NPCs survived and the majority of them differentiated into oligodendrocytes. In contrast to the prevalent oligodendroglial differentiation in case of the NPC/MSC co-transplantation, naïve NPCs transplanted in the absence of MSCs differentiated predominantly into astrocytes. In summary, the pro-oligodendrogenic activity of MSCs was maintained only after co-transplantation into hippocampal slice cultures. Therefore, in the otherwise astrogenic milieu, MSCs established an oligodendrogenic niche for transplanted NPCs, and thus, co-transplantation of MSCs with NPCs might provide an attractive approach to re-myelinate the various regions of the diseased CNS. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Ample evidence points to the dentate gyrus as anatomical region for persistent neurogenesis in the adult mammalian brain. This has been confirmed in a variety of animal models under physiological as well as pathophysiological conditions. Notwithstanding, similar experiments are difficult to perform in humans. Postmortem studies demonstrated persisting neurogenesis in the elderly human brain. In addition, neural precursor cells can be isolated from surgical specimens obtained from patients with intractable temporal lobe epilepsy (TLE) and propagated or differentiated into neuronal and glial lineages. It remains a controversial issue, whether epileptic seizures have an effect on or even increase hippocampal neurogenesis in humans. Recent data support the notion that seizures induce neurogenesis in young patients, whereas the capacity of neuronal recruitment and proliferation decreases with age. Animal models of TLE further indicate that these newly generated neurons integrate into epileptogenic networks and contribute to increased seizure susceptibility. However, pathomorphological disturbances within the epileptic hippocampus, such as granule cell dispersion (GCD), may not directly result from compromised neurogenesis. Still, the majority of adult TLE patients present with significant dentate granule cell loss at an end stage of the disease, which relates to severe memory and learning disabilities. In conclusion, surgical specimens obtained from TLE patients represent an important tool to study mechanisms of stem cell recruitment, proliferation and differentiation in the human brain. In addition, increasing availability of surgical specimens opens new avenues to systematically explore disease pathomechanisms in chronic epilepsies. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) is routinely used for diagnosing and monitoring neurological diseases. The CSF proteins used so far for diagnostic purposes (except for those associated with whole cells) are soluble. Here, we show that human CSF contains specific membrane particles that carry prominin- 1/CD133, a neural stem cell marker implicated in brain tumors, notably glioblastoma. Differential and equilibrium centrifugation and detergent solubility analyses showed that these membrane particles were similar in physical properties and microdomain organization to small membrane vesicles previously shown to be released from neural stem cells in the mouse embryo. The levels of membrane particle-associated prominin-1/CD133 declined during childhood and remained constant thereafter, with a remarkably narrow range in healthy adults. Glioblastoma patients showed elevated levels of membrane particle- associated prominin-1/CD133, which decreased dramatically in the final stage of the disease. Hence, analysis of CSF for membrane particles carrying the somatic stem cell marker prominin-1/CD133 offers a novel approach for studying human central nervous system disease. [ABSTRACT FROM AUTHOR]

Activation of the Wnt/wingless signalling cascade is a key mechanism in developmental morphogenesis, whereas aberrant nuclear accumulation of β-catenin in adult tissues seems to be associated with neoplastic transformation and tumour progression. Adamantinomatous craniopharyngiomas carry activating mutations in exon 3 of the β-catenin gene, which results in a distinct pattern of nuclear β-catenin accumulation in up to 95% of respective tumour specimens. To better characterise the impact of nuclear β-catenin aggregation in these neoplasms, we systematically examined epithelial differentiation and cell cycle-associated molecules in accumulating compared to non-accumulating tumour cell clusters using a cohort of 65 adamantinomatous craniopharyngiomas. Monoclonal antibodies directed against cytokeratins 5/6 (CK5/6) were utilised to differentiate squamous from simple epithelium, the latter being identified by immunoreactivity for cytokeratins 8 and 18 (CK8/CK18). Intriguingly, nuclear β-catenin accumulation in whorl-like tumour cell clusters was always associated with a distinct CK8 and CK18 immunoreactivity, whereas surrounding non-accumulating tumour cells showed exclusively squamous differentiation indicated by CK5/6 expression. In addition, a low proliferation activity combined with an increased expression of p21WAF1/CIP1, a key control protein of the cell cycle, was observed in β-catenin accumulating cells. Our data support an impact of nuclear β-catenin on different cytoarchitectural and epithelial differentiation patterns in adamantinomatous craniopharyngiomas. [ABSTRACT FROM AUTHOR]

Chromatin modification plays a key role in fate decision of neural stem cells. Here, we explored the impact of epigenetic remodelling onto neuronal fate determination using specific inhibitors of histone deacetylases (iHDAC). Adult subventricular zone (SVZ) precursor cells were expanded as neurospheres and treated in vitro with second generation iHDAC MS-275, M344 and suberoylanilide hydroxamic acid (SAHA). All tested compounds revealed a significant increase of βIII-tubulin positive neurons (ranging from 258 to 431%) in a concentration-dependent manner. The number of oligodendrocytes was decreased by almost 50%, accompanied by a reduction of Olig2 mRNA expression. In contrast, astrocyte quantity remained unaffected after iHDAC treatment. Both control and iHDAC treated cells expressed markers of mature GABAergic and dopaminergic neurons. Increased expression levels of NeuroD, Cyclin D2 and B-lymphocyte translocation gene 3 (Btg3) point to a shift towards neuronal fate determination targeted by HDAC inhibitors. [ABSTRACT FROM AUTHOR]

Radial glia-like (RGL) stem cells persist in the adult mammalian hippocampus, where they generate new neurons and astrocytes throughout life. The process of adult neurogenesis is well documented, but cell-autonomous factors regulating neuronal and astroglial differentiation are incompletely understood. Here, we evaluate the functions of the transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells. Genetic deletion of Zeb1 causes a shift toward symmetric cell division that consumes the RGL cell and generates pro-neuronal progenies, resulting in an increase of newborn neurons and a decrease of newly generated astrocytes. We identify ZEB1 as positive regulator of the ets-domain transcription factor ETV5 that is critical for asymmetric division. [Display omitted] • The stem cell transcription factor, ZEB1, demarcates active from quiescent RGL cells • ZEB1 drives the self-renewal of RGL cells by promoting asymmetric cell division • Loss of Zeb1 causes increased neurogenesis and decreased astrogliogenesis • ZEB1 induces Etv5 expression to regulate asymmetric cell division Gupta et al. show that the stem cell transcription factor, ZEB1, labels activated hippocampal stem cells and regulates their self-renewal and astroglial fate specification. Mechanistically, ZEB1 promotes asymmetric cell divisions and induces the expression of ETV5, a transcriptional regulator of asymmetric divisions and astroglial lineage commitment. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most lethal brain cancer in adults, with no known cure. This cancer is characterized by a pronounced genetic heterogeneity, but aberrant activation of receptor tyrosine kinase signaling is among the most frequent molecular alterations in glioblastoma. Somatic mutations of fibroblast growth factor receptors (FGFRs) are rare in these cancers, but many studies have documented that signaling through FGFRs impacts glioblastoma progression and patient survival. Small-molecule inhibitors of FGFR tyrosine kinases are currently being trialed, underlining the therapeutic potential of blocking this signaling pathway. Nevertheless, a comprehensive overview of the state of the art of the literature on FGFRs in glioblastoma is lacking. Here, we review the evidence for the biological functions of FGFRs in glioblastoma, as well as pharmacological approaches to targeting these receptors. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast‐cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow‐cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose‐deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7‐related metabolic pathways is a viable therapeutic strategy. Synopsis: Transcriptomic and metabolomic profiling of primary brain tumor cells demonstrate that functionally different glioblastoma (GBM) cell subpopulations depend on distinct metabolic pathways for their growth and survival. More invasive slow cycling tumor cells rely on oxidative phosphorylation and lipid metabolism, suggesting targetable candidates for the inhibition of treatment‐resistant tumors. Patient‐derived GBM cells contain fast‐cycling cells (FCCs) relying on aerobic glycolysis and slow‐cycling cells (SCCs) depending on mitochondrial oxidative phosphorylation in vivo.SCCs show increased resistance, invasion, and metabolic gene signatures characteristic of recurrent tumors.SCCs show increased levels of metabolites and components involved in lipid metabolism, storage, and transport.Block of FABP7‐dependent exogenous fatty acid uptake decreases resistance of SCCs to chemotherapy and glucose deprivation. Oxidative phosphorylation and lipid metabolism specify distinct energetic set‐up of invasive brain tumor cells. [ABSTRACT FROM AUTHOR]