Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en inhibant la signalisation NF-κB, le disulfirame prévient la formation de micrométastases d'un glioblastome multiforme
Glioblastoma Multiforme (GBM), the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here it is demonstrated that the invasive phenotype of GBM is orchestrated by the transcription factor NF-κB which, via metalloproteinases (MMPs), regulates Fibronectin (Fn) processing. Both, cell lines and tumor stem cells from primary GBM, secrete high levels of Fn and when cleaved by MMPs form an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, GBM cells are licensed to invade their surroundings. Mechanistic study revealed that NF-κB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane (CAM) assay. Furthermore, having delineated the underlying molecular mechanism of GBM invasion, the potential of a Disulfiram-based therapy was revealed in a highly invasive orthotrophic GBM mouse model. Implications: This study defines a novel therapeutic approach that inhibits micrometastases invasion and reverts lethal Glioblastoma into a less aggressive disease.