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

Autor:	Philippe Aretz, Donata Maciaczyk, Suad Yusuf, Rüdiger V. Sorg, Daniel Hänggi, Hongjia Liu, Hongde Liu, Tikam Chand Dakal, Amit Sharma, Ramakrishna Bethanabatla, Silke Neumann, Jarek Maciaczyk
Rok vydání:	2022
Předmět:	Brain Neoplasms Organic Chemistry General Medicine Monocytes Catalysis Computer Science Applications Inorganic Chemistry Cell Line Tumor Leukocytes Mononuclear Tumor Microenvironment Humans glioblastoma GSCs β-catenin Wnt CCL2 monocytes immune evasion MSAB Physical and Theoretical Chemistry Glioblastoma Wnt Signaling Pathway Molecular Biology Chemokine CCL2 beta Catenin Spectroscopy Cell Proliferation
Zdroj:	International Journal of Molecular Sciences; Volume 23; Issue 9; Pages: 4562
ISSN:	1422-0067
DOI:	10.3390/ijms23094562
Popis:	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.
Databáze:	OpenAIRE
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