Gain of 20q11.21 in human pluripotent stem cells impairs TGF-β-dependent neuroectodermal commitment

Gain of 20q11.21 is one of the most common recurrent genomic aberrations in human pluripotent stem cells. Although it is known that overexpression of the antiapoptotic gene Bcl-xL confers a survival advantage to the abnormal cells, their differentiation capacity has not been fully investigated. RNA sequencing of mutant and control hESC lines, and a line transgenically overexpressing Bcl-xL, shows that overexpression of Bcl-xL is sufficient to cause most transcriptional changes induced by the gain of 20q11.21. Moreover, the differentially expressed genes in mutant and Bcl-xL overexpressing lines are enriched for genes involved in TGF-beta- and SMAD-mediated signaling, and neuron differentiation. Finally, we show that this altered signaling has a dramatic negative effect on neuroectodermal differentiation, while the cells maintain their ability to differentiate to mesendoderm derivatives. These findings stress the importance of thorough genetic testing of the lines before their use in research or the clinic

Impact of Solute Carrier Transporters in Glioma Pathology: A Comprehensive Review

Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management. © 2023 by the authors

Targeting of endoplasmic reticulum (ER) stress in gliomas

Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past decade, extracellular stress and intracellular DNA damage have been shown to disturb proteostasis leading to Endoplasmic Reticulum (ER) stress that is implicated in the regulation of gene expression and the pathogenesis of several tumor types, including gliomas. Upon ER stress induction, neoplastic cells activate the adaptive mechanism of unfolded protein response (UPR), an integrated signaling system that either restores ER homeostasis or induces cell apoptosis. Recently, the manipulation of the UPR has emerged as a new therapeutic target in glioma treatment. General UPR activators or selective GRP78, ATF6 and PERK inducers have been detected to modulate cell proliferation and induce apoptosis of glioma cells. At the same time, target-specific UPR inhibitors and small molecule proteostasis disruptors, work in reverse to increase misfolded proteins and cause a dysregulation in protein maturation and sorting, thus preventing the growth of neoplastic cells. Herein, we discuss the pathogenic implication of ER stress in gliomas onset and progression, providing an update on the current UPR modifying agents that can be potentially used in glioma treatment. © 2020 Elsevier Lt

Histone Methyltransferase SETDB1: A Common Denominator of Tumorigenesis with Therapeutic Potential

Epigenetic regulation of gene expression has been ultimately linked to cancer development, with posttranslational histone modifications representing attractive targets for disease monitoring and therapy. Emerging data have demonstrated histone lysine (K) methylation by methyltransferase SETDB1 as a common denominator of gene regulation in several cancer types. SETDB1 reversibly catalyzes the di- and trimethylation of histone 3 (H3) K9 in euchromatic regions of chromosomes, inhibiting gene transcription within these regions and promoting a switch from euchromatic to heterochromatic states. Recent studies have implicated aberrant SETDB1 activity in the development of various types of cancers, including brain, head and neck, lung, breast, gastrointestinal, ovarian, endometrial and prostate cancer, mesothelioma, melanoma, leukemias, and osteosarcoma. Although its role has not been fully elucidated in every case, most data point toward a pro-oncogenic potential of SETDB1 via the downregulation of critical tumor-suppressive genes. Less commonly, however, SETDB1 can also acquire a tumor-suppressive role, depending on cancer type and stage. Here we provide an updated overview of the cellular and molecular effects underlying SETDB1 activity in cancer development and progression along with current targeting strategies in different cancer types, with promising effects either as a standalone therapy or in conjunction with other therapeutic agents. ©2020 American Association for Cancer Research

Insights in the immunobiology of glioblastoma

Abstract: Glioblastoma, a grade IV astrocytoma, is considered as the most malignant intracranial tumor, characterized by poor prognosis and therapy resistance. Tumor heterogeneity that often leads to distinct functional phenotypes contributes to glioblastoma (GB) indispensable growth and aggressiveness. The complex interaction of neoplastic cells with tumor microenvironment (TME) along with the presence of cancer stem-like cells (CSCs) largely confers to extrinsic and intrinsic GB heterogeneity. Recent data indicate that glioma cells secrete a variety of soluble immunoregulatory factors to attract different cell types to TME including astrocytes, endothelial cells, circulating stem cells, and a range of immune cells. These further induce a local production of cytokines, chemokines, and growth factors which upon crosstalk with extracellular matrix (ECM) components reprogram immune cells to inflammatory or anti-inflammatory phenotypes and manipulate host’s immune response in favor of cancer growth and metastasis. Herein, we provide an overview of the immunobiologic factors that orchestrate the complex network of glioma cells and TME interactions in an effort to identify potential therapeutic targets for GB malignancy. Current therapeutic schemes and advances in targeting GB-TME crosstalk are further discussed. Key messages: • Intrinsic and extrinsic tumor heterogeneity affects GB growth and aggressiveness. • GB cells secrete growth factors and chemoattractants to recruit immune cells to TME. • GAMs are a critical cell type in promoting GB growth. • GAMs change from pro-inflammatory, anti-tumor M1 phenotype to pro-tumorigenic M2. • Novel therapeutic agents target the crosstalk of neoplastic cells with TME. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature

Glioma Cells Expressing High Levels of ALDH5A1 Exhibit Enhanced Migration Transcriptional Signature in Patient Tumors

Accumulating data shows that altered metabolic activity contributes to glioma development. Recently, modulation of SSADH (succinic semialdehyde dehydrogenase) expression, implicated in the catabolism of GABA neurotransmitter, was shown to impact glioma cell properties, such as proliferation, self-renewal and tumorigenicity. The purpose of this study was to investigate the clinical significance of SSADH expression in human gliomas. Using public single-cell RNA-sequencing data from glioma surgical resections, we initially grouped cancer cells according to ALDH5A1 (Aldehyde dehydrogenase 5 family member A1) expression, which encodes SSADH. Gene ontology enrichment analysis of genes differentially expressed between cancer cells expressing high or low levels of ALDH5A1, highlighted enrichment in genes implicated in cell morphogenesis and motility. In glioblastoma cell lines, ALDH5A1 knockdown inhibited cell proliferation, induced apoptosis and reduced their migratory potential. This was accompanied by a reduction in the mRNA levels of the adherens junction molecule ADAM-15 and deregulation in the expression of EMT biomarkers, with increased CDH1 and decreased vimentin mRNA levels. Evaluation of SSADH expression in a cohort of 95 gliomas using immunohistochemistry showed that SSADH expression was significantly elevated in cancer tissues compared to normal brain tissues, without any significant correlation with clinicopathological characteristics. In summary, our data show that SSADH is upregulated in glioma tissues irrespective of the histological grade and its expression sustains glioma cell motility. © 2023, The American Society for Experimental Neurotherapeutics, Inc

Female accountants in partnership positions: Persona non grata?

Purpose – Although the proportion of women accountants is rising steadily, their number in partnership position remains constant. This article explores this phenomenon in an attempt (a) to identify the reasons behind it and (b) clarify which are the barriers that hinder female accountants from being in the top echelon of the accounting practice in an emerging economy like Cyprus. Methodology/approach – The study reported in this article builds on two previous studies, quantitative in nature, carried out by one of the present authors. Utilising the findings of the two earlier studies, the authors use a qualitative approach to further explore the reasons as to why there is a ‘concrete wall’ for women in accounting practices at partnership level. Findings – In contrast to other studies, the present study found that the prohibiting factor creating the barrier is not motherhood but the cultural attitudes and expectations of men imposed on mothers. Another finding is that despite the fact that there is a bigger pool of women today in senior manager positions, it is uncertain if the proportion of female partners will rise in a decade. Research limitations – Although the qualitative study utilising interviews of both genders identified interesting concerns for the local accounting profession, these findings cannot be representative of all emerging economies. Practical implications – The article adds to existing knowledge by clarifying the reasons discouraging women accountants from reaching partnership positions. Findings are of interest to industry stakeholders who wish (a) to attract more women accountants to partnership positions and (b) to develop an environment that addresses women's concerns and enhances their career aspirations towards reaching the top echelon of their profession. Originality/value of article – Most research in this field utilises quantitative or qualitative research independently. In this research we utilise the results of the quantitative studies to indentify in depth the ‘real’ rather than the ‘imaginary’ barrier facing women accountants from entering partnership. Furthermore, this is the first time this is studied in an emerging economy, whereas all other studies are in developed economies