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Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
Scott Haston1, Estela Gonzalez-Gualda2, Samir Morsli2
1Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK.
Abstract:
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.
Insights
Senescent cells, particularly macrophages, drive lung cancer initiation and progression via the senescence-associated secretory phenotype (SASP). Targeting these senescent cells or macrophages significantly reduces tumor burden and improves survival in lung cancer models.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Senescent cells accumulate in tumors, promoting cancer via the senescence-associated secretory phenotype (SASP).
- Identifying specific senescent cell types and their roles in lung cancer is crucial for therapeutic development.
Purpose of the Study:
- To investigate the predominant senescent cell types in KRAS-driven lung tumors.
- To characterize the pro-tumorigenic functions of senescent macrophages.
- To evaluate therapeutic strategies targeting senescent cells and macrophages in lung cancer.
Main Methods:
- Utilized a p16-FDR mouse line for studying senescent cells in lung tumors.
- Employed single-cell transcriptomics to identify senescent cell populations and SASP factors.
- Investigated the effects of genetic/senolytic ablation of senescent cells and macrophage depletion on tumor progression.
Main Results:
- Macrophages and endothelial cells were identified as major senescent cell types in murine lung tumors.
- A distinct population of tumor-associated macrophages expressing pro-tumorigenic SASP factors was characterized.
- Targeting senescent cells or macrophages significantly reduced tumor burden and improved survival.
- Senescent macrophages were found in human pre-malignant lung lesions but not adenocarcinomas.
Conclusions:
- Senescent macrophages play a critical role in the initiation and progression of KRAS-driven lung cancer.
- Targeting senescent macrophages presents a promising therapeutic avenue for lung cancer.
- These findings suggest potential cancer preventative strategies focusing on senescent cell modulation.
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