Al Delbany Diana, Duong Mai Chi, Regin Marius, Sarkar Arkajyoti, Radi Ayoub, Lefort Anne, Libert Frédérick, Parmentier Marc, Spits Claudia
Research Group Genetics, Reproduction and Development, Faculty of Medicine and Pharmacy, Brussels Health Campus, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
Department of Biochemistry, Military Hospital 175, 786 Nguyen Kiem Street, Ho Chi Minh City 71409, Vietnam.
Biomolecules. 2025 Aug 11;15(8):1150. doi: 10.3390/biom15081150.
C-C motif chemokine receptor-like 2 (CCRL2) is an atypical chemokine receptor (ACKR) that binds chemerin with high affinity but lacks classical G protein-coupled signaling. Instead, it functions as a non-signaling presenter of chemerin to CMKLR1-expressing cells, modulating antitumor immunity. CCRL2 is highly expressed in the tumor microenvironment and various human cancers, and its expression has been linked to delayed tumor growth in mouse models, primarily through the chemerin/CMKLR1 axis. While CCRL2's role in immune surveillance is well established, its tumor cell-intrinsic functions remain less clear. Here, we investigated the impact of CCRL2 overexpression and knockout on tumor cell behavior in vitro. Although CCRL2 did not affect proliferation, migration, or clonogenicity in B16F0 melanoma and LLC cells, it significantly influenced spheroid morphology in B16F0 cells. Transcriptomic analysis revealed that CCRL2 modulates innate immune signaling pathways, including TLR4 and IFN-γ/STAT1, with context-dependent downstream effects. These findings suggest that CCRL2 shapes tumor architecture by rewiring inflammatory signaling networks in a cell-intrinsic manner. Further studies in other cancer types and cell models are needed to determine whether CCRL2's regulatory role is broadly conserved and to explore its potential as a therapeutic target in solid tumors.
C-C基序趋化因子受体样2（CCRL2）是一种非典型趋化因子受体（ACKR），它能与chemerin高亲和力结合，但缺乏经典的G蛋白偶联信号传导。相反，它作为chemerin的非信号呈递分子作用于表达CMKLR1的细胞，调节抗肿瘤免疫。CCRL2在肿瘤微环境和多种人类癌症中高表达，其表达在小鼠模型中与肿瘤生长延迟有关，主要通过chemerin/CMKLR1轴。虽然CCRL2在免疫监视中的作用已得到充分证实，但其在肿瘤细胞内在功能方面仍不太清楚。在这里，我们研究了CCRL2过表达和敲除对体外肿瘤细胞行为的影响。尽管CCRL2不影响B16F0黑色素瘤细胞和LLC细胞的增殖、迁移或克隆形成能力，但它显著影响B16F0细胞的球体形态。转录组分析显示，CCRL2以依赖于背景的下游效应调节包括TLR4和IFN-γ/STAT1在内的固有免疫信号通路。这些发现表明，CCRL2通过以细胞内在方式重塑炎症信号网络来塑造肿瘤结构。需要在其他癌症类型和细胞模型中进行进一步研究，以确定CCRL2的调节作用是否广泛保守，并探索其作为实体瘤治疗靶点的潜力。
