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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 (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]

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]

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]