دورية أكاديمية
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
| العنوان: | Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. |
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| المؤلفون: | Haston S; 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., Gonzalez-Gualda E; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK., Morsli S; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK., Ge J; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK., Reen V; 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., Calderwood A; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK., Moutsopoulos I; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK., Panousopoulos L; Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK., Deletic P; Division of Medicine, University College London, London, UK., Carreno G; Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK., Guiho R; Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK., Manshaei S; Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK., Gonzalez-Meljem JM; Tecnologico de Monterrey, School of Engineering and Sciences, Mexico City, Mexico., Lim HY; Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK., Simpson DJ; MRC Human Generics Unit, University of Edinburgh, Edinburgh, UK., Birch J; 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., Pallikonda HA; 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., Chandra T; MRC Human Generics Unit, University of Edinburgh, Edinburgh, UK., Macias D; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK., Doherty GJ; Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK., Rassl DM; Royal Papworth Hospital NHS Foundation Trust. Cambridge Biomedical Campus, Cambridge CB2 0AY, UK., Rintoul RC; 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., Signore M; Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK., Mohorianu I; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK., Akbar AN; Division of Medicine, University College London, London, UK., Gil J; 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., Muñoz-Espín D; 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., Martinez-Barbera JP; 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. |
| المصدر: | Cancer cell [Cancer Cell] 2023 Jul 10; Vol. 41 (7), pp. 1242-1260.e6. Date of Electronic Publication: 2023 Jun 01. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101130617 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-3686 (Electronic) Linking ISSN: 15356108 NLM ISO Abbreviation: Cancer Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, Mass. : Cell Press, c2002- |
| مواضيع طبية MeSH: | Cellular Senescence*/genetics , Lung Neoplasms*/genetics , Lung Neoplasms*/metabolism, Aged ; Animals ; Humans ; Mice ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Endothelial Cells ; Macrophages/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Tumor Microenvironment |
| مستخلص: | 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. Competing Interests: Declaration of interests J.G. has acted as a consultant for Unity Biotechnology, Geras Bio, Myricx Pharma, and Merck KGaA. J.G. owns equity in Geras Bio. J.G. is a named inventors in an MRC patent and a named inventor in another Imperial College patents, both related to senolytic therapies (the patents are not related to the work presented here). Unity Biotechnology, Myricx Pharma, and Pfizer have funded research in J.G.’s laboratory (unrelated to the work presented here). (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Comment in: Cancer Cell. 2023 Jul 10;41(7):1201-1203. (PMID: 37267952) Comment in: Cancer Discov. 2023 Aug 4;13(8):1758. (PMID: 37326376) Comment in: Nat Aging. 2023 Jul;3(7):757. (PMID: 37414988) |
| معلومات مُعتمدة: | BRC-1215-20014 United Kingdom DH_ Department of Health; RG86786 United Kingdom CRUK_ Cancer Research UK; MR/R000530/1 United Kingdom MRC_ Medical Research Council; C62187/A26989 United Kingdom CRUK_ Cancer Research UK; MR/T030534/1 United Kingdom MRC_ Medical Research Council; C54322/A27727 United Kingdom CRUK_ Cancer Research UK; 26989 United Kingdom CRUK_ Cancer Research UK; 29760 United Kingdom CRUK_ Cancer Research UK; C9685/A25117 United Kingdom CRUK_ Cancer Research UK; C15075/A28647 United Kingdom CRUK_ Cancer Research UK; 28647 United Kingdom CRUK_ Cancer Research UK; C62187/A29760 United Kingdom CRUK_ Cancer Research UK; United Kingdom DH_ Department of Health; 27727 United Kingdom CRUK_ Cancer Research UK; MC_U120085810 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: ABT-737; NSCLC; aging; cancer; endothelial cells; immunosuppression; macrophages; p16INK4a; senescence; senolytic |
| المشرفين على المادة: | 0 (KRAS protein, human) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) EC 3.6.5.2 (Hras protein, mouse) |
| تواريخ الأحداث: | Date Created: 20230602 Date Completed: 20230718 Latest Revision: 20240320 |
| رمز التحديث: | 20240320 |
| DOI: | 10.1016/j.ccell.2023.05.004 |
| PMID: | 37267953 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1878-3686 |
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| DOI: | 10.1016/j.ccell.2023.05.004 |