1. Crosstalk between β-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells.
- Author
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Aretz P, Maciaczyk D, Yusuf S, Sorg RV, Hänggi D, Liu H, Liu H, Dakal TC, Sharma A, Bethanabatla R, Neumann S, and Maciaczyk J
- Subjects
- Cell Line, Tumor, Cell Proliferation, Humans, Leukocytes, Mononuclear metabolism, Monocytes metabolism, Tumor Microenvironment, Wnt Signaling Pathway, Brain Neoplasms metabolism, Chemokine CCL2 genetics, Chemokine CCL2 pharmacology, Glioblastoma genetics, Glioblastoma metabolism, beta Catenin genetics, beta Catenin metabolism
- Abstract
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, β-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of β-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in β-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting β-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 shβ-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as β-catenin knockdown. When investigating the effect of CCL2 on β-catenin activity, we found that CCL2 modulates components of the Wnt/β-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological β-catenin inhibitor MSAB reduces active β-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that β-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between β-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence.
- Published
- 2022
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