Abstract：
BACKGROUND: Tumor-associated macrophages (TAM) exert a significant influence on the progression and heterogeneity of various subtypes of breast cancer (BRCA). However, the roles of heterogeneous TAM within BRCA subtypes remain unclear. Therefore, this study sought to elucidate the role of TAM across the following three BRCA subtypes: triple-negative breast cancer, luminal, and HER2.
METHODS: This investigation aimed to delineate the variations in marker genes, drug sensitivity, and cellular communication among TAM across the three BRCA subtypes. We identified specific ligand-receptor (L-R) pairs and downstream mechanisms regulated by VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Experimental verification of these pairs was conducted by co-culturing macrophages with three subtypes of BRCA cells.
RESULTS: Our findings reveal the heterogeneity of macrophages within the three BRCA subtypes, evidenced by variations in marker gene expression, composition, and functional characteristics. Notably, heterogeneous TAM were found to promote invasive migration and epithelial-mesenchymal transition (EMT) in MDA-MB-231, MCF-7, and SKBR3 cells, activating NF-κB pathway via P38 MAPK, TGF-β1, and AKT, respectively, through distinct VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Inhibition of these specific L-R pairs effectively reversed EMT, migration, and invasion of each cancer cells. Furthermore, we observed a correlation between ligand gene expression and TAM sensitivity to anticancer drugs, suggesting a potential strategy for optimizing personalized treatment guidance.
CONCLUSIONS: Our study highlights the capacity of heterogeneous TAM to modulate biological functions via distinct pathways mediated by specific L-R pairs within diverse BRCA subtypes. This study might provide insights into precision immunotherapy of different subtypes of BRCA.
METHODS: This investigation aimed to delineate the variations in marker genes, drug sensitivity, and cellular communication among TAM across the three BRCA subtypes. We identified specific ligand-receptor (L-R) pairs and downstream mechanisms regulated by VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Experimental verification of these pairs was conducted by co-culturing macrophages with three subtypes of BRCA cells.
RESULTS: Our findings reveal the heterogeneity of macrophages within the three BRCA subtypes, evidenced by variations in marker gene expression, composition, and functional characteristics. Notably, heterogeneous TAM were found to promote invasive migration and epithelial-mesenchymal transition (EMT) in MDA-MB-231, MCF-7, and SKBR3 cells, activating NF-κB pathway via P38 MAPK, TGF-β1, and AKT, respectively, through distinct VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Inhibition of these specific L-R pairs effectively reversed EMT, migration, and invasion of each cancer cells. Furthermore, we observed a correlation between ligand gene expression and TAM sensitivity to anticancer drugs, suggesting a potential strategy for optimizing personalized treatment guidance.
CONCLUSIONS: Our study highlights the capacity of heterogeneous TAM to modulate biological functions via distinct pathways mediated by specific L-R pairs within diverse BRCA subtypes. This study might provide insights into precision immunotherapy of different subtypes of BRCA.
摘要：
背景：肿瘤相关巨噬细胞（TAM）对乳腺癌（BRCA）的各种亚型的进展和异质性具有重要影响。然而,异质性TAM在BRCA亚型中的作用尚不清楚.因此,这项研究试图阐明TAM在以下三种BRCA亚型中的作用：三阴性乳腺癌，管腔,和HER2。
方法：这项研究旨在描绘标记基因的变异，药物敏感性,以及TAM之间跨三种BRCA亚型的蜂窝通信。我们鉴定了由VEGFA-VEGFR1、SPP1-CD44和SPP1-ITGB1L-R对调节的特异性配体-受体(L-R)对和下游机制。通过将巨噬细胞与BRCA细胞的三种亚型共培养来进行这些对的实验验证。
结果：我们的发现揭示了三种BRCA亚型中巨噬细胞的异质性，标记基因表达的变化证明，composition,和功能特征。值得注意的是,发现异质TAM促进MDA-MB-231，MCF-7和SKBR3细胞的侵袭性迁移和上皮间质转化（EMT），通过P38MAPK激活NF-κB通路，TGF-β1和AKT，分别,通过不同的VEGFA-VEGFR1、SPP1-CD44和SPP1-ITGB1L-R对。抑制这些特定的L-R对有效逆转EMT，迁移,和每个癌细胞的侵袭。此外，我们观察到配体基因表达与TAM对抗癌药物的敏感性之间的相关性，提出了优化个性化治疗指导的潜在策略。
结论：我们的研究强调了异质TAM通过不同BRCA亚型中特定L-R对介导的不同途径调节生物学功能的能力。这项研究可能为BRCA不同亚型的精准免疫疗法提供见解。
方法：这项研究旨在描绘标记基因的变异，药物敏感性,以及TAM之间跨三种BRCA亚型的蜂窝通信。我们鉴定了由VEGFA-VEGFR1、SPP1-CD44和SPP1-ITGB1L-R对调节的特异性配体-受体(L-R)对和下游机制。通过将巨噬细胞与BRCA细胞的三种亚型共培养来进行这些对的实验验证。
结果：我们的发现揭示了三种BRCA亚型中巨噬细胞的异质性，标记基因表达的变化证明，composition,和功能特征。值得注意的是,发现异质TAM促进MDA-MB-231，MCF-7和SKBR3细胞的侵袭性迁移和上皮间质转化（EMT），通过P38MAPK激活NF-κB通路，TGF-β1和AKT，分别,通过不同的VEGFA-VEGFR1、SPP1-CD44和SPP1-ITGB1L-R对。抑制这些特定的L-R对有效逆转EMT，迁移,和每个癌细胞的侵袭。此外，我们观察到配体基因表达与TAM对抗癌药物的敏感性之间的相关性，提出了优化个性化治疗指导的潜在策略。
结论：我们的研究强调了异质TAM通过不同BRCA亚型中特定L-R对介导的不同途径调节生物学功能的能力。这项研究可能为BRCA不同亚型的精准免疫疗法提供见解。
