NRASdestines tumor cells to the lungs.
The lungs are frequently affected by cancer metastasis. AlthoughNRASmutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross-examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference andNRASoverexpression, identified NRAS signaling partners by microarray, and validated them usingCxcr1- andCxcr2-deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressedNRASpromotes lung colonization by regulating interleukin-8-related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells. Our results support a model whereNRAS-mutant, chemokine-expressing circulating tumor cells target the CXCR1-expressing lung vasculature and recruit CXCR2-expressing myeloid cells to initiate metastasis. We further describe a clinically relevant approach to prevent NRAS-driven pulmonary metastasis by inhibiting chemokine signaling. In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL-8-related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Anastasios D
AD
Giannou
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Antonia
A
Marazioti
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Nikolaos I
0000-0002-0065-2282
NI
Kanellakis
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Ioanna
I
Giopanou
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Ioannis
I
Lilis
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Dimitra E
DE
Zazara
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Giannoula
G
Ntaliarda
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Danai
D
Kati
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Vasileios
V
Armenis
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Georgia A
GA
Giotopoulou
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Anthi C
AC
Krontira
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Marina
M
Lianou
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Theodora
T
Agalioti
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.|Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Member of the German Center for Lung Research (DZL), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Munich, Germany.
Malamati
M
Vreka
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
Maria
M
Papageorgopoulou
Pneumology Unit, Department of Pediatrics, Faculty of Medicine, University of Patras, Rio, Greece.
Sotirios
S
Fouzas
Department of Radiation Oncology and Stereotactic Radiotherapy, Faculty of Medicine, University of Patras, Rio, Greece.
Dimitrios
D
Kardamakis
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.|Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
Ioannis
I
Psallidas
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece magsp@upatras.gr gstathop@upatras.gr stathopoulos@helmholtz-muenchen.de.
Magda
0000-0003-2505-7778
M
Spella
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece magsp@upatras.gr gstathop@upatras.gr stathopoulos@helmholtz-muenchen.de.|Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Member of the German Center for Lung Research (DZL), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Munich, Germany.
Georgios T
0000-0002-9215-6461
GT
Stathopoulos
D000818:Animals; D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016209:Interleukin-8 / Q000276:immunology; D008168:Lung / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000276:immunology / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins; D009154:Mutation; D015398:Signal Transduction; D015854:Up-Regulation
D016209:Interleukin-8; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse
inflammation and cancer; interleukin‐8‐related chemokines; lung endothelium; myeloid cells; pulmonary metastasis