Crosstalk between β-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, beta-catenin was associated with sternness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of beta-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in beta-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting beta-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by sh beta-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as beta-catenin knockdown. When investigating the effect of CCL2 on beta-catenin activity, we found that CCL2 modulates components of the Wnt/beta-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological beta-catenin inhibitor MSAB reduces active beta-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that beta-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between beta-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence.

Automated summary

The study reveals the crucial role of beta-catenin in attracting monocytes towards GBM cells and suggests that the interaction between beta-catenin and CCL2 may contribute to the maintenance of GSCs by modulating immune cell interaction and promoting GBM growth and recurrence.