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作者：SCI天天读
SCI
21 June 2023
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
(IF: Cancer Cell, 38.585)
Haston S, Gonzalez-Gualda E, Morsli S, Ge J, Reen V, Calderwood A, Moutsopoulos I, Panousopoulos L, Deletic P, Carreno G, Guiho R, Manshaei S, Gonzalez-Meljem JM, Lim HY, Simpson DJ, Birch J, Pallikonda HA, Chandra T, Macias D, Doherty GJ, Rassl DM, Rintoul RC, Signore M, Mohorianu I, Akbar AN, Gil J, Muñoz-Espín D, Martinez-Barbera JP. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell. 2023 May 26:S1535-6108(23)00172-1. doi: 10.1016/j.ccell.2023.05.004. Epub ahead of print. PMID: 37267953.
Correspondence：scott.haston.13@ucl.ac.uk (S.H.), dm742@cam.ac.uk (D.M.-E.), j.martinez-barbera@ucl.ac.uk (J.P.M.-B.)
The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.
在肿瘤微环境中，衰老细胞的积累可以通过衰老相关分泌表型（SASP）以一种旁分泌方式驱动肿瘤发生。利用新的p16-FDR小鼠系，我们发现巨噬细胞和内皮细胞是小鼠KRAS驱动型肺部肿瘤中主要的衰老细胞类型。通过单细胞转录组学，我们鉴定了一组表达一系列促肿瘤SASP因子和表面蛋白的肿瘤相关巨噬细胞，这种细胞也存在于正常老化的肺中。在KRAS 驱动型肺癌模型中，衰老细胞的遗传或衰老消融，或巨噬细胞耗竭可显着降低肿瘤负荷并提高生存活率。此外，我们揭示了具有衰老特征的巨噬细胞在人类肺部恶性前期病变中的存在，但在腺癌中不存在。综上所述，我们的研究结果揭示了衰老巨噬细胞在癌症发生和发展中的重要作用，突出了潜在的治疗途径和癌症预防策略。
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原文地址：http://mp.weixin.qq.com/s?src=11×tamp=1687370806&ver=4604&signature=*vBl*jx51AwtmdCeK-0Hc*UMPteQTs-V1sjoEw9S3j9OSdSHTh*3SfVKkj-p-uWfilHCmBWDfZl1zNiMgYru-UGa1RPEke1CbfjUrIUsaKJh5zk2AMlBp-2iQ1TdzGqC&new=1 |
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