Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7. Suppression of NMD activity led to the re-expression of dozens of PTC mRNAs. Amongst these, several encoded mutant proteins with putative deleterious activity against MSI tumorigenesis (e.g., HSP110DE9 chaperone mutant). Inhibition of NMD in vivo using amlexanox reduced MSI tumor growth, but not that of MSS tumors. These results suggest that inhibition of the oncogenic activity of NMD may be an effective strategy for the personalized treatment of MSI CRC.

L’instabilité des séquences répétées du génome (appelées microsatellites) est une conséquence de l’inactivation fonctionnelle du système de réparation des erreurs produites au cours de la réplication de l’ADN (système MMR,mismatch repair). Elle signe un phénotype tumoral fréquent appelé MSI (microsatellite instable) qui a été mis en évidence il y a un peu plus de 20 ans. Les cancers MSI sont fréquents chez l’homme, associés à de nombreuses localisations primitives (côlon, estomac, endomètre, etc.). Ils peuvent être héréditaires ou, le plus souvent, de survenue sporadique. Cet article propose une synthèse des travaux dédiés à l’étude des cancers MSI menés par des chercheurs et médecins français récompensés par le prix Jean et Madeleine Schaeverbeke de la Fondation de France. Depuis 20 ans, leur activité a grandement contribué à améliorer nos connaissances sur ce mode original de tumorigenèse, jetant les bases d’une médecine personnalisée de ces tumeurs chez l’homme, en pleine émergence aujourd’hui.

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.