Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK.
Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
Cancer Cell. 2023 Jul 10;41(7):1242-1260.e6. doi: 10.1016/j.ccell.2023.05.004. Epub 2023 Jun 1.
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.
衰老细胞在肿瘤微环境中的积累可以通过衰老相关分泌表型（SASP）以旁分泌的方式驱动肿瘤发生。利用一种新的 p16-FDR 小鼠品系，我们表明巨噬细胞和内皮细胞是 KRAS 驱动的肺肿瘤中主要的衰老细胞类型。通过单细胞转录组学，我们鉴定出一群肿瘤相关巨噬细胞，它们表达独特的促肿瘤 SASP 因子和表面蛋白，并且也存在于正常老年肺中。衰老细胞的基因或化学消融，或巨噬细胞耗竭，导致 KRAS 驱动的肺癌模型中的肿瘤负担显著减少和生存率提高。此外，我们揭示了在人类肺前恶性病变中存在具有衰老特征的巨噬细胞，但在腺癌中不存在。总之，我们的研究结果揭示了衰老巨噬细胞在肺癌的发生和发展中的重要作用，强调了潜在的治疗途径和癌症预防策略。
