Endothelial Secreted Factors Suppress Mitogen Deprivation-Induced Autophagy and Apoptosis in Glioblastoma Stem-Like Cells

International audienceRapidly growing and highly vascularized tumors, such as glioblastoma multiforme, contain heterogeneous areas within the tumor mass, some of which are inefficiently supplied with nutrients and oxygen. While the cell death rate is elevated in such zones, tumor cells are still suspected to grow and survive independently of extracellular growth factors. In line with this, glioblastoma stem-like cells (GSCs) are found closely associated with brain vasculature in situ, and as such are most likely in a protected microenvironment. However, the behavior of GSCs under deprived conditions has not been explored in detail. Using a panel of 14 patient-derived GSCs, we report that ex vivo mitogen deprivation impaired self-renewal capability, abolished constitutive activation of the mTor pathway, and impinged on GSC survival via the engagement of autophagic and apoptotic cascades. Moreover, pharmacological inhibition of the mTor pathway recapitulated the mitogen deprivation scenario. In contrast, blocking either apoptosis or autophagy, or culturing GSCs with endothelial-secreted factors partly restored mTor pathway activation and rescued GSC survival. Overall, our data suggest that GSCs are addicted to mTor, as their survival and self-renewal are profoundly dependent on this signaling axis. Thus, as mTor governs the fate of GSCs under both deprivation conditions and in the presence of endothelial factors, it could be a key target for therapeutic purposes

Managing expectations, rights, and duties in large-scale genomics initiatives: a European comparison

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

A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

International audienceGlioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intrace-rebral tumors in NOD-SCID-IL2Rc (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplan-tations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor

The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation

Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence.The authors thank members of the LRP for helpful discussions and are indebted to V. Barroca and the staff of the animal facilities and to N. Deschamps and J. Baijer for cell sorting. We also thanks I. Naguibneva for the gift of the pTRIP shHIF1α plasmid. MS is the recipient of a doctoral fellowship from the Ministère de la Recherche. This work was supported by grants from CEA (Segment Radiobiologie), La Ligue contre le Cancer (Comité d’Ile de France), Electricité de France (EDF), Fondation de France (N° Engt: 2013-00042632) and Ramón y Cajal program (RYC-2013-13450)