Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
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DOI：
10.1016/j.ccell.2023.05.004
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发表时间：
2023-07-10
期刊：
影响因子：
50.3
通讯作者：
Martinez-Barbera, Juan Pedro
中科院分区：
文献类型：
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作者：
Haston, Scott;Gonzalez-Gualda, Estela;Martinez-Barbera, Juan Pedro
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）以旁分泌方式驱动肿瘤发生。使用新的p16-FDR小鼠系，我们表明巨噬细胞和内皮细胞是小鼠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，我们确定了一个群体的肿瘤相关的巨噬细胞，表达一个独特的阵列的促肿瘤SASP因子和表面蛋白，也存在于正常老化的肺。衰老细胞的遗传或衰老清除或巨噬细胞耗竭导致KRAS驱动的肺癌模型中肿瘤负荷显著降低和存活率增加。此外，我们揭示了在人肺癌前病变中存在具有衰老特征的巨噬细胞，但在腺癌中没有。总之，我们的研究结果揭示了衰老巨噬细胞在肺癌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。
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.