Haston, Scott;
Gonzalez-Gualda, Estela;
Morsli, Samir;
Ge, Jianfeng;
Reen, Virinder;
Calderwood, Alexander;
Moutsopoulos, Ilias;
... Martinez-Barbera, Juan Pedro; + view all
(2023)
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
Cancer Cell
10.1016/j.ccell.2023.05.004.
(In press).
Preview |
Text
1-s2.0-S1535610823001721-main.pdf - Published Version Download (11MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ccell.2023.05.004 |
| Publisher version: | https://doi.org/10.1016/j.ccell.2023.05.004 |
| Language: | English |
| Additional information: | © 2023 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | ABT-737, NSCLC, aging, cancer, endothelial cells, immunosuppression, macrophages, p16INK4a, senescence, senolytic |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171888 |
Archive Staff Only
 |
View Item |
