Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

• Published in: Oncogene 2022-05, Vol.41 (21), p.3024-3036
• Main Authors: Wu, Jianqi, Shen, Shuai, Liu, Tianqi, Ren, Xiufang, Zhu, Chen, Liang, Qingyu, Cui, Xiao, Chen, Ling, Cheng, Peng, Cheng, Wen, Wu, Anhua
• Format: Article
• Language: English
• Subjects: 13; 13/31; 13/51; 38/1; 38/109; 38/39; 42/100; 631/67/1922; 631/67/395; 64/60; 692/53/2422; 82/80; Apoptosis; Autocrine signalling; Brain cancer; Cell Biology; Chemokines - genetics; Chemoresistance; Genotype & phenotype; Glioblastoma; Glioblastoma - pathology; Human Genetics; Humans; Internal Medicine; Macrophages; Medicine; Medicine & Public Health; Mesenchyme; Metastases; NF-kappa B; NF-κB protein; Oncology; Paracrine signalling; Phenotypes; Proteasomes; Receptors, Chemokine; Tumor cells; Tumor Microenvironment; Tumor-Associated Macrophages; Ubiquitin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02295-w

Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have suggested that there is a positive correlation between the GBM mesenchymal status and immune cell infiltration. However, the mechanisms by which GBM acquires its mesenchymal features in a tumor immune microenvironment-dependent manner remains unknown. Here, we uncovered a chemerin-mediated autocrine and paracrine network by which the mesenchymal phenotype of GBM cells is strengthened. We identified chemerin as a prognostic secretory protein mediating the mesenchymal phenotype-promoting network between tumor-associated macrophages (TAMs) and tumor cells in GBM. Mechanistically, chemerin promoted the mesenchymal features of GBM by suppressing the ubiquitin-proteasomal degradation of CMKLR1, a chemerin receptor predominantly expressed on TAMs and partially expressed on GBM cells, thereby enhancing NF-κB pathway activation. Moreover, chemerin was found to be involved in the recruitment of TAMs in the GBM tumor microenvironment. We revealed that chemerin also enhances the mesenchymal phenotype-promoting ability of TAMs and promotes their M2 polarization via a CMKLR1/NF-κB axis, which further exacerbates the mesenchymal features of GBM. Blocking the chemerin/CMKLR1 axis with 2-(α-naphthoyl) ethyltrimethylammonium iodide disrupted the mesenchymal network and suppressed tumor growth in GBM. These results suggest the therapeutic potential of targeting the chemerin/CMKLR1 axis to block the mesenchymal network in GBM.