Using two KRAS-driven lung p16INK4a reporter models, Haston et al. showed that although at early stage of tumorigenesis, KRAS-transformed cells expressed p16INK4a, a majority of the identified p16INK4a-expressing cells in tumorigenic lungs were macrophages (Mθ) and to a lesser extent endothelial cells, showing a signature of cellular senescence and SASP. Similar Mθ expressing senescence markers were also observed in aged mice and in early-stage human NSCLC tumors. Ablation of p16INK4a-expressing cells decreased Mθ and intratumoral vascular networks, increased intratumoral CD8+ T cells, and reduced lung tumor burden.
Contributed by Shishir Pant
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.
Author Info: (1) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: scott.haston.13@ucl.ac.uk. (2
Author Info: (1) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: scott.haston.13@ucl.ac.uk. (2) Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK. (3) Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK. (4) Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK. (5) MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. (6) Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. (7) Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. (8) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. (9) Division of Medicine, University College London, London, UK. (10) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. (11) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. (12) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. (13) Tecnologico de Monterrey, School of Engineering and Sciences, Mexico City, Mexico. (14) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. (15) MRC Human Generics Unit, University of Edinburgh, Edinburgh, UK. (16) MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. (17) MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. (18) MRC Human Generics Unit, University of Edinburgh, Edinburgh, UK. (19) Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK. (20) Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. (21) Royal Papworth Hospital NHS Foundation Trust. Cambridge Biomedical Campus, Cambridge CB2 0AY, UK. (22) Royal Papworth Hospital NHS Foundation Trust. Cambridge Biomedical Campus, Cambridge CB2 0AY, UK; Department of Oncology, University of Cambridge, Cambridge, UK; CRUK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK. (23) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. (24) Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. (25) Division of Medicine, University College London, London, UK. (26) MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. (27) Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK; CRUK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK. Electronic address: dm742@cam.ac.uk. (28) Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: j.martinez-barbera@ucl.ac.uk.
