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Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro . Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032). The oncolytic virus Delta-24-RGD is in clinical trial for adult glioma. Here, the authors show that this virus elicits an immune response in mouse models of pediatric high-grade glioma and diffuse pontine intrinsic glioma, resulting in improved survival.

Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients’ glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients’ tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients’ tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients’ tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.

The increasing availability of brain data within and outside the biomedical field, combined with the application of artificial intelligence (AI) to brain data analysis, poses a challenge for ethics and governance. We identify distinctive ethical implications of brain data acquisition and processing, and outline a multi-level governance framework. This framework is aimed at maximizing the benefits of facilitated brain data collection and further processing for science and medicine whilst minimizing risks and preventing harmful use. The framework consists of four primary areas of regulatory intervention: binding regulation, ethics and soft law, responsible innovation, and human rights.

Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients’ single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.

This article reports on the findings of an international workshop organised by the UK-France Genomics and Ethics Network (UK-FR GENE) in 2021. They focus specifically on how collection, storage and sharing of genomic data may pose challenges to established principles and values such as trust, confidentiality, and privacy in countries that have implemented, or are about to implement, large-scale national genomic initiatives. These challenges impact the relationships between patients/citizens and medicine/science, and on each party’s rights and duties towards each other. Our geographic scope of comparative analysis includes initiatives underway in England (Genomics England), France (Plan France Médecine Génomique) and Germany (German Human Genome-Phenome Archive). We discuss existing as well as future challenges raised by large-scale health data collection and management in each country. We conclude that the prospects of improving individualised patient healthcare as well as contributing to the scientific and research prosperity of any given nation engaged in health data collection, storage and processing are undeniable. However, we also attempt to demonstrate that biomedical data requires careful management, and transparent and accountable governance structures that are clearly communicated to patients/participants and citizens. Furthermore, when third parties partake as stakeholders, transparent consent protocols relative to data access and use come centre stage, and patient benefits must clearly outweigh commercial interests. Finally, any cross-border data transfer needs to be carefully managed to address incoherencies between regional, national, and supranational regulations and recommendations.

Macrophage migration inhibitory factor (MIF) plays an important role in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs); however, the downstream effectors of this factor remain unknown. Here, we show that MIF increases the expression of Pax6 and Chd7 in NSPCs in vitro. During neural development, the chromatin remodeling factor Chd7 (chromatin helicase-DNA-binding protein 7) is expressed in the ventricular zone of the telencephalon of mouse brain at embryonic day 14.5, as well as in cultured NSPCs. Retroviral overexpression of Pax6 in NSPCs increased Chd7 gene expression. Lentivirally-expressed Chd7 shRNA suppressed cell proliferation and neurosphere formation, and inhibited neurogenesis in vitro, while decreasing gene expression of Hes5 and N-myc. In addition, CHD7 overexpression increased cell proliferation in human embryonic stem cell-derived NSPCs (ES-NSPCs). In Chd7 mutant fetal mouse brains, there were fewer intermediate progenitor cells (IPCs) compared to wildtype littermates, indicating that Chd7 contributes to neurogenesis in the early developmental mouse brain. Furthermore, in silico database analysis showed that, among members of the CHD family, CHD7 is highly expressed in human gliomas. Interestingly, high levels of CHD7 gene expression in human glioma initiating cells (GICs) compared to normal astrocytes were revealed and gene silencing of CHD7 decreased GIC proliferation. Collectively, our data demonstrate that CHD7 is an important factor in the proliferation and stemness maintenance of NSPCs, and CHD7 is a promising therapeutic target for the treatment of gliomas.