دورية أكاديمية
MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.
| العنوان: | MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. |
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| المؤلفون: | Brägelmann J; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. johannes.braegelmann@uni-koeln.de.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. johannes.braegelmann@uni-koeln.de.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. johannes.braegelmann@uni-koeln.de.; Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. johannes.braegelmann@uni-koeln.de., Lorenz C; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Borchmann S; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Else-Kröner-Forschungskolleg Clonal Evolution in Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Nishii K; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Wegner J; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Meder L; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Ostendorp J; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Ast DF; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Heimsoeth A; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Nakasuka T; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Hirabae A; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Okawa S; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Dammert MA; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Plenker D; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, 11724, USA., Klein S; Else-Kröner-Forschungskolleg Clonal Evolution in Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Lohneis P; Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Gu J; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Godfrey LK; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Forster J; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; Genome Informatics, Institute of Human Genetics, University Duisburg-Essen, Essen, Germany., Trajkovic-Arsic M; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Zillinger T; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Haarmann M; Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Quaas A; Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Lennartz S; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Schmiel M; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., D'Rozario J; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Thomas ES; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Imperial College London, London, UK., Li H; Crown Bioscience, San Diego, CA, USA., Schmitt CA; Department of Hematology, Oncology and Tumor Immunology, Charité - University Medical Center, Virchow Campus, and Molekulares Krebsforschungszentrum, Berlin, Germany.; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Department of Hematology and Oncology, Kepler University Hospital, Johannes Kepler University, Linz, Austria., George J; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department of Head and Neck Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Thomas RK; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany., von Karstedt S; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Hartmann G; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Büttner R; Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Ullrich RT; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany., Siveke JT; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Ohashi K; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.; Department of Respiratory Medicine, Okayama University Hospital, Japan, 2-5-1 Shikata-cho, Kitaku, Okayama, 700-8558, Japan., Schlee M; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Sos ML; Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. martin.sos@uni-koeln.de.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. martin.sos@uni-koeln.de.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. martin.sos@uni-koeln.de. |
| المصدر: | Nature communications [Nat Commun] 2021 Sep 17; Vol. 12 (1), pp. 5505. Date of Electronic Publication: 2021 Sep 17. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [London] : Nature Pub. Group |
| مواضيع طبية MeSH: | Immunity, Innate*/drug effects , MAP Kinase Signaling System*/drug effects, DEAD Box Protein 58/*metabolism , Inflammation/*pathology , Neoplasms/*metabolism , Protein Kinase Inhibitors/*pharmacology , Receptors, Immunologic/*metabolism, Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cell Cycle Checkpoints/drug effects ; Cell Death/drug effects ; Cell Line, Tumor ; Cytokines/metabolism ; ErbB Receptors/metabolism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Immune Evasion/drug effects ; Interferon Regulatory Factor-1/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplasms/pathology ; Oncogenes ; Signal Transduction/drug effects |
| مستخلص: | Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8 + T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. (© 2021. The Author(s).) |
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| معلومات مُعتمدة: | P30 CA045508 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Adaptor Proteins, Signal Transducing) 0 (Cytokines) 0 (IRF1 protein, human) 0 (Interferon Regulatory Factor-1) 0 (MAVS protein, human) 0 (Protein Kinase Inhibitors) 0 (Receptors, Immunologic) EC 2.7.10.1 (ErbB Receptors) EC 3.6.1.- (RIGI protein, human) EC 3.6.4.13 (DEAD Box Protein 58) |
| تواريخ الأحداث: | Date Created: 20210918 Date Completed: 20211012 Latest Revision: 20240403 |
| رمز التحديث: | 20240403 |
| مُعرف محوري في PubMed: | PMC8448826 |
| DOI: | 10.1038/s41467-021-25728-8 |
| PMID: | 34535668 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 2041-1723 |
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| DOI: | 10.1038/s41467-021-25728-8 |