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

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.

Glioma-associated microglia/macrophages (GAMs) in glioblastoma: Immune function in the tumor microenvironment and implications for immunotherapy

“…The role of MCP-1 in GAMs has been verified by various in vivo and in vitro studies, where the MCP-1 expression level is highly correlated with the grade of glioma ( 66 ). A recent study indicated that the cooperation between β- Catenin and MCP-1 may be responsible for the rapid and highly heterogeneous growth of Isocitrate dehydrogenase wildtype GBM ( 72 ). M-CSF is another important chemokine, which not only promotes the mobility of GAMs but also mediates the M2 polarization of GAMs ( 73 ).…”

Multiomics integration reveals the effect of Orexin A on glioblastoma

“…CCL2 and its related receptor (CCR2) promote the migration of brain tumors and monocytes across the vascular endothelium (Vakilian et al, 2017;Cho et al, 2019). Besides, Aretz et al (Aretz et al, 2022) demonstrated that the cross-talk between CCL2 and β-catenin could affect the dryness and immune escape mechanism of GBM by regulating the activity of immune cells and glioblastoma stem cells. In animal models, mNOX-E36 blocked angiogenesis and macrophage recruitment, and tumor volume and blood volume were reduced.…”

Nanoparticles Hitchhike on Monocytes for Glioblastoma Treatment after Low-Dose Radiotherapy

“…Endogenous cells are potentially powerful tools for delivering therapeutic agents to specific brain targets. − Bone marrow-derived circulating monocytes (BMDMs) are the primary source of TAMs in GBMs, with the natural ability to traverse the BBB/BTB and penetrate brain tumor sites, and they mainly target vascular-free, necrotic/hypoxic areas in tumors . RT, as the mainstay for brain tumor management, − can promote chemotaxis of monocytes by upregulating monocyte chemokine-1 (MCP-1)/C-C basal chemokine ligand 2 (CCL-2) expression in the tumor region. , Therefore, it can be hypothesized that monocytes can act as carriers to deliver drugs to brain tumors in the presence of chemokines.…”