Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.

Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment.

Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells.

Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes.

The promise of DNA damage response inhibitors for the treatment of glioblastoma.

Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM.

Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer.

The natural history of small cell lung cancer (SCLC) includes rapid evolution from chemosensitivity to chemoresistance, although mechanisms underlying this evolution remain obscure due to scarcity of post-relapse tissue samples. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) via single-cell RNAseq of chemo-sensitive and -resistant CDXs and patient CTCs. We found globally increased ITH including heterogeneous expression of therapeutic targets and potential resistance pathways, such as EMT, between cellular subpopulations following treatment-resistance.

Depletion of CLK2 sensitizes glioma stem-like cells to PI3K/mTOR and FGFR inhibitors.

The Cdc2-like kinases (CLKs) regulate RNA splicing and have been shown to suppress cell growth. Knockdown of CLK2 was found to block glioma stem-like cell (GSC) growth through the AKT/FOXO3a/p27 pathway without activating mTOR and MAPK signaling, suggesting that these pathways mediate resistance to CLK2 inhibition. We identified CLK2 binding partners using immunoprecipitation assays and confirmed their interactions in GSCs.

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance.

Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types-including neutrophils and myeloid-derived suppressor cells-that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects.

The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells.

Background: Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).

Results: The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR).

Targeting intercellular adhesion molecule-1 prolongs survival in mice bearing bevacizumab-resistant glioblastoma.

Intercellular cell adhesion molecule 1 (ICAM-1; also known as CD54) is overexpressed in bevacizumab-resistant glioblastoma. In the present study, we tested our hypothesis that highly expressed ICAM-1 mediates glioblastoma's resistance to antiangiogenic therapy. We validated ICAM-1 overexpression in tumors resistant to antiangiogenic therapy using real-time polymerase chain reaction, immunohistochemistry, and Western blotting.

GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma.

A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype.

Characterization and comparison of osteoblasts derived from mouse embryonic stem cells and induced pluripotent stem cells.

New developments in stem cell biology offer alternatives for the reconstruction of critical-sized bone defects. One of these developments is the use of induced pluripotent stem (iPS) cells. These stem cells are similar to embryonic stem (ES) cells, but can be generated from adult somatic cells and therefore do not raise ethical concerns.

Aberrant mesenchymal differentiation of glioma stem-like cells: implications for therapeutic targeting.

Differentiation has been proposed as a therapeutic strategy for glioblastoma (GBM) in part due to observations of stem-like cells in GBM that have been shown to undergo terminal differentiation in response to growth factor withdrawal and BMP activation. However, the effects of long term exposure to serum culture conditions on glioma sphere cultures/glioma stem-like cells (GSCs) have not been examined. Here we show that GSCs retained both neurosphere formation and tumor initiation abilities after short or long term serum exposure.

Multipotent stem cell factor UGS148 is a marker for tanycytes in the adult hypothalamus.

The present study describes for the first time the neural expression and distribution of UGS148, a protein encoded by the RIKEN cDNA63330403K07 gene that has been shown to be prominently and characteristically expressed in neural stem cells (NSCs). Based on its molecular structure, UGS148 is an intracellular protein expected to be involved in intracellular sorting, trafficking, exocytosis and membrane insertion of proteins. We demonstrate that UGS148 is highly expressed in embryonic NSCs as well as, albeit at low level, in the adult neurogenic niches, the subventricular zone and the hippocampal dentate gyrus.

Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis.

Glioblastoma (GBM) is the most common brain tumor in adults and the mesenchymal GBM subtype was reported to be the most malignant, presenting severe hypoxia and necrosis. Here, we investigated the possible role of a hypoxic microenvironment for inducing a mesenchymal and invasive phenotype. The exposure of non-mesenchymal SNB75 and U87 cells to hypoxia induced a strong change in cell morphology that was accompanied by enhanced invasive capacity and the acquisition of mesenchymal marker expression.

Subclassification of newly diagnosed glioblastomas through an immunohistochemical approach.

Molecular signatures in Glioblastoma (GBM) have been described that correlate with clinical outcome and response to therapy. The Proneural (PN) and Mesenchymal (MES) signatures have been identified most consistently, but others including Classical (CLAS) have also been reported. The molecular signatures have been detected by array techniques at RNA and DNA level, but these methods are costly and cannot take into account individual contributions of different cells within a tumor.

Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma.

Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes.

TGF-β as a therapeutic target in high grade gliomas - promises and challenges.

Transforming growth factor-β (TGF-β) is a cytokine with a key role in tissue homeostasis and cancer. TGF-β elicits both tumor suppressive and tumor promoting functions during cancer progression, in a wide range of cancers. Here, we review the tumor promoting function of TGF-β and its possible promise as a therapeutic target in high grade gliomas, including glioblastoma multiforme (GBM), a disease with very poor prognosis.

Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway.

Glioma stem-like cells (GSCs) may be the initiating cells in glioblastoma (GBM) and contribute to the resistance of these tumors to conventional therapies. Development of novel chemotherapeutic agents and treatment approaches against GBM, especially those specifically targeting GSCs are thus necessary. In the present study, we found that a novel Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway inhibitor (WP1193) significantly decreased the proliferation of established glioma cell lines in vitro and inhibit the growth of glioma in vivo.

The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.

Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs.

Differentiation of induced pluripotent stem cells into functional oligodendrocytes.

The technology to generate autologous pluripotent stem cells (iPS cells) from almost any somatic cell type has brought various cell replacement therapies within clinical research. Besides the challenge to optimize iPS protocols to appropriate safety and GMP levels, procedures need to be developed to differentiate iPS cells into specific fully differentiated and functional cell types for implantation purposes. In this article, we describe a protocol to differentiate mouse iPS cells into oligodendrocytes with the aim to investigate the feasibility of IPS stem cell-based therapy for demyelinating disorders, such as multiple sclerosis.

Oligodendrocyte differentiation and implantation: new insights for remyelinating cell therapy.

Purpose Of Review: Recent research on oligodendrocyte development has yielded new insights on the involvement of morphogens and differentiation factors in oligodendrogenesis. This knowledge has improved strategies to control neural stem cell-derived oligodendrocyte differentiation and functional maturation in vitro. In this review, we highlight the current knowledge on oligodendrocyte differentiation and discuss the novel possibilities of neural stem cell-derived oligodendrocytes for graft-based remyelination therapy, for example, for multiple sclerosis.

Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2.

The mechanisms underlying the regulation of neural stem cell (NSC) renewal and maintenance of their multipotency are still not completely understood. Self-renewal of stem cells in general implies repression of genes that encode for cell lineage differentiation. Enhancer of zeste homolog 2 (Ezh2) is a Polycomb group protein involved in stem cell renewal and maintenance by inducing gene silencing via histone methylation and deacetylation.

Isolation and culture of rat and mouse oligodendrocyte precursor cells.

The ability to isolate oligodendroglial precursor cells (OPCs) provides a powerful means to characterize their differentiation, properties and potential for myelin repair. Although much knowledge is available for isolation of OPCs from the rat central nervous system, preparation and maintenance of mouse OPCs has been until recently a challenge owing to difficulties in obtaining a sufficient quantity of purified OPCs. Here, we describe protocols to prepare highly enriched rat OPCs and nearly homogenous mouse OPCs.

Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes.

Differentiation induction of neural stem cells (NSCs) into oligodendrocytes during embryogenesis is the result of a complex interaction between local induction factors and intracellular transcription factors. At the early stage of differentiation, in particular, the helix-loop-helix transcription factors Olig1 and Olig2 have been shown to be essential for oligodendrocyte lineage determination. In view of the possible application of NSCs as a source for remyelinating cell transplants in demyelinating diseases (e.