Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells

Therapies targeting cancer metastasis are challenging owing to the complexity of the metastatic process and the high number of effectors involved. Although tumour hypoxia has previously been associated with increased aggressiveness as well as resistance to radio- and chemotherapy, the understanding of a direct link between the level and duration of hypoxia and the individual steps involved in metastasis is still missing. Using live imaging in a chick embryo model, we have demonstrated that the exposure of neuroblastoma cells to 1% oxygen for 3 days was capable of (1) enabling cell migration towards blood vessels, (2) slowing down their velocity within blood vessels to facilitate extravasation and (3) promoting cell proliferation in primary and secondary sites. We have shown that cells do not have to be hypoxic anymore to exhibit these acquired capabilities as a long-term memory of prior hypoxic exposure is kept. Furthermore, non-hypoxic cells can be influenced by neighbouring hypoxic preconditioned cells and be entrained in the metastatic progression. The acquired aggressive phenotype relies on hypoxia-inducible factor (HIF)-dependent transcription of a number of genes involved in metastasis and can be impaired by HIF inhibition. Altogether, our results demonstrate the need to consider both temporal and spatial tumour heterogeneity because cells can 'remember' an earlier environment and share their acquired phenotype with their close neighbours. As a consequence, it is necessary to monitor the correct hypoxic markers to be able to predict the consequences of the cells' history on their behaviour and their potential response to therapies

p53-mediated delayed NF-κB activity enhances etoposide-induced cell death in medulloblastoma

Medulloblastoma (MB) is an embryonic brain tumour that arises in the cerebellum. Using several MB cell lines, we have demonstrated that the chemotherapeutic drug etoposide induces a p53- and caspase-dependent cell death. We have observed an additional caspase-independent cell death mechanism involving delayed nuclear factor κB (NF-κB) activity. The delayed induction was controlled by a p53-dependent transcription step and the production of death receptors (especially CD95/Fas). We further demonstrated that in both MB and glioblastoma (GM) cell lines, in which the p53 pathway was not functional, no p65 activation could be detected upon etoposide treatment. MB cell lines that have mutations in p53 or NF-κB are either less sensitive (NF-κB mutant) or even completely resistant (p53 mutant) to chemotherapeutic intervention. The optimal cell death was only achieved when both p53 and NF-κB were switched on. Taken together, our results shed light on the mechanism of NF-κB activation by etoposide in brain tumours and show that the genetic background of MB and GM cells determines their sensitivity to chemotherapy and has to be taken into account for efficient therapeutic intervention

Live Imaging of Cell Invasion Using a Multicellular Spheroid Model and Light-Sheet Microscopy.

Three-dimensional cellular assays are becoming increasingly popular as a fundamental tool to bridge the gap between tissue culture systems and in vivo tissue. In particular, spheroids are recognised today as a necessary intermediate model between testing in monolayer cultures and testing in animals. This chapter describes a straightforward protocol, from sample preparation to image acquisition and initial post-processing, based on one of most widely used commercial light-sheet fluorescence microscopy platform, the Zeiss Lightsheet Z.1

Initiation à la microélectronique ultime CMOS

Dans cet article, nous présentons un projet proposé en 1ère année de master et permettant d'appréhender le contexte de la microélectronique CMOS, avec en particulier les enjeux actuels de la miniaturisation des composants. Pour cela, les étudiants mettent en oeuvre des logiciels de simulation physique de transistors et pratiquent la réalisation technologique de structures élémentaires en salle blanche, objets qui sont ensuite caractérisés électriquement

The role of hypoxia-inducible factor post-translational modifications in regulating its localisation, stability, and activity

Abstract The hypoxia signalling pathway enables adaptation of cells to decreased oxygen availability. When oxygen becomes limiting, the central transcription factors of the pathway, hypoxia-inducible factors (HIFs), are stabilised and activated to induce the expression of hypoxia-regulated genes, thereby maintaining cellular homeostasis. Whilst hydroxylation has been thoroughly described as the major and canonical modification of the HIF-α subunits, regulating both HIF stability and activity, a range of other post-translational modifications decorating the entire protein play also a crucial role in altering HIF localisation, stability, and activity. These modifications, their conservation throughout evolution, and their effects on HIF-dependent signalling are discussed in this review

Face value in A Tale of Two Cities

This essay considers how proper names and faces construct, destruct, and reconstruct social identity in A tale of two cities. Manette’s identification at the start of the novel, for example, occurs chiefly through a recalled proper name and face. As the French Revolution worked to destroy privileged, individuated identities, so too have contemporary theories of identity, which dismiss individual identity and remain preoccupied with identity at the level of common nouns and generic bodies. However, the near escape of Louis XVI in 1791 highlighted the failure of common noun categorisations and generic bodies to establish social identity. Named and disguised as a valet, Louis was identified by the resemblance of his embodied face to its representation on the money of the period. This picture-identification ushered in a law requiring facial descriptions in passports. Madame Defarge’s knitted register follows pattern of these descriptions. The nearly identical faces of Darnay and Carton, however, thwart her attempts at picture-identification. Where the shared family name and face condemn Darnay by association, physiognomical resemblance to the unrelated Carton saves him. It rescues not only Darnay but also Carton from legal, moral, female, and lower-class condemnation, allowing the French aristocrat to escape public guilt by family, class, and national association and the degraded English middle-class professional to emerge sanitised from his private moral guilt as an international, intergenerational hero. The process operates under a model of simile. Simile, eschewing the metaphoric merger and metonymic displacement reserved for women and the lower classes in the novel, allows each man to exchange his guilt for the other man’s innocence and innocence for the other man’s guilt. It ushers in a perpetual identity theft that allows the individual sins and class crimes of ruling males to pass unaccounted for and be refigured as innocence and heroism