GSE126658
Plexin-B2 reduces glioma cell cohesion and regulates glioma-vascular interactions
The diffuse invasion of glioblastoma (GBM) cells into healthy brain tissue is a main contributor for the high lethality of this most frequent form of malignant brain tumor. Plexins are cell surface receptors for semaphorins and control cell adhesion and cytoskeletal dynamics in development and in adult physiology. Gene expression of Plexin-B2 is upregulated in GBM and correlates with its lethality. We show here that Plexin-B2 activity can reduce the cohesiveness of GBM cells, which facilitates their invasive capacity. Targeted deletion of Plexin-B2 in GBM cells increased their cohesion to each other, revealing that a major function of Plexin-B2 activity is to downregulate cell-cell adhesion, possibly by downregulating other cell adhesion systems. In an in vivo intracranial transplant model, invasion of Plexin-B2 mutant GBM cells was impaired, with cells invading shorter distances. Interestingly, the loss of Plexin-B2 also changed the migration mode of cells, with the balance of cells in brain stroma vs. capillary space shifted: Plexin-B2 mutant cells were more likely to adhere to the vasculature. Our structure-function analyses revealed that the Ras-GAP domain of Plexin-B2 that is the main functional output responsible for the cohesion regulating function of Plexin-B2. Transcriptomic analyses of Plexin-B2 KO cells suggests that Plexin-B2 loss in different GBM cell lines has no direct transcriptional target genes, however, consistently, cell adhesion molecules were changed in expression, suggesting that cells compensate for loss of Plexin-B2. Thus, Plexin-B2 acts as a key regulator of the cohesiveness of GBM cells, thereby facilitating their invasiveness. Overall design: GBM cell lines with knockout mutations of Plexin-B2