Mutant KRAS promotes malignant pleural effusion formation

Theodora Agalioti, Anastasios D. Giannou, Anthi C. Krontira, Nikolaos I. Kanellakis, Danai Kati, Malamati Vreka, Mario Pepe, Magda Spella, Ioannis Lilis, Dimitra E. Zazara, Eirini Nikolouli, Nikolitsa Spiropoulou, Andreas Papadakis, Konstantina Papadia, Apostolos Voulgaridis, Vaggelis Harokopos, Panagiota Stamou, Silke Meiners, Oliver Eickelberg, Linda A. Snyder, Sophia G. Antimisiaris, Dimitrios Kardamakis, Ioannis Psallidas, Antonia Marazioti and Georgios T. Stathopoulos ()
Additional contact information
Theodora Agalioti: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Anastasios D. Giannou: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Anthi C. Krontira: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Nikolaos I. Kanellakis: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Danai Kati: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Malamati Vreka: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Mario Pepe: Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Magda Spella: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Ioannis Lilis: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Dimitra E. Zazara: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Eirini Nikolouli: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Nikolitsa Spiropoulou: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Andreas Papadakis: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Konstantina Papadia: Laboratory for Pharmaceutical Technology, School of Health Sciences, University of Patras, and Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT
Apostolos Voulgaridis: Rio University Hospital, Faculty of Medicine, University of Patras
Vaggelis Harokopos: Genomics Facility, Biomedical Sciences Research Center ‘Alexander Fleming’
Panagiota Stamou: Faculty of Medicine, University of Patras
Silke Meiners: Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Oliver Eickelberg: Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Linda A. Snyder: Oncology Discovery Research, Janssen R&D LLC
Sophia G. Antimisiaris: Laboratory for Pharmaceutical Technology, School of Health Sciences, University of Patras, and Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT
Dimitrios Kardamakis: Faculty of Medicine, University of Patras
Ioannis Psallidas: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Antonia Marazioti: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
Georgios T. Stathopoulos: Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

Date: 2017
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DOI: 10.1038/ncomms15205

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