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Giannou, A.D.* ; Marazioti, A.* ; Kanellakis, N.I.* ; Giopanou, I.* ; Lilis, I.* ; Zazara, D.E.* ; Ntaliarda, G.* ; Kati, D.* ; Armenis, V.* ; Giotopoulou, G.A.* ; Krontira, A.C.* ; Lianou, M.* ; Agalioti, T.* ; Vreka, M. ; Papageorgopoulou, M.* ; Fouzas, S.* ; Kardamakis, D.* ; Psallidas, I.* ; Spella, M.* ; Stathopoulos, G.T.

NRAS destines tumor cells to the lungs.

EMBO Mol. Med. 9, 672-686 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The lungs are frequently affected by cancer metastasis. Although NRAS mutations 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 and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1- and Cxcr2-deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes 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 where NRAS-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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Inflammation And Cancer ; Interleukin‐8‐related Chemokines ; Lung endothelium ; Myeloid Cells ; Pulmonary Metastasis; Breast-cancer Cells; Metastatic Niche; Survival Signals; Stem-cells; Mutation; Ras; Melanoma; Angiogenesis; Growth; Pathways
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Journal EMBO Molecular Medicine
Quellenangaben Volume: 9, Issue: 5, Pages: 672-686 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Chichester
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)