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Giopanou, I.* ; Kanellakis, N.I.* ; Giannou, A.D.* ; Lilis, I.* ; Marazioti, A.* ; Spella, M.* ; Papaleonidopoulos, V.* ; Simoes, D.C.M.* ; Zazara, D.E.* ; Agalioti, T.* ; Moschos, C.* ; Magkouta, S.* ; Kalomenidis, I.* ; Panoutsakopoulou, V.* ; Lamort, A.-S. ; Stathopoulos, G.T.

Osteopontin drives KRAS-mutant lung adenocarcinoma.

Carcinogenesis 41, 1134-1144 (2019)
Verlagsversion Postprint Forschungsdaten DOI PMC
Open Access Green
Increased expression of osteopontin (secreted phosphoprotein 1, SPP1) is associated with aggressive human lung adenocarcinoma (LADC), but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced LADC. We combined mouse models of tobacco carcinogen-induced LADC, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis. Co-expression of Spp1 and mutant Kras(G12C) in benign cells was employed to investigate SPP1/KRAS interactions in oncogenesis. Finally, intratracheal adenovirus encoding Cre recombinase was delivered to LSL.KRAS(G12D) mice lacking endogenous or overexpressing transgenic Spp1 alleles. SPP1 was overexpressed in experimental and human LADC and portended poor survival. In response to two different smoke carcinogens, Spp1-deficient mice developed fewer and smaller LADC with decreased cellular survival and angiogenesis. Both lung epithelial- and macrophage-secreted SPP1 drove tumor-associated inflammation, while epithelial SPP1 promoted early tumorigenesis by fostering the survival of KRAS-mutated cells. Finally, loss and overexpression of Spp1 was, respectively, protective and deleterious for mice harboring KRAS(G12D)-driven LADC. Our data support that SPP1 is functionally involved in early stages of airway epithelial carcinogenesis driven by smoking and mutant KRAS and may present an important therapeutic target.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Kras ; Spp1 ; Lung Cancer ; Survival ; Urethane; Early-stage; Cancer; Promotes; Expression; Resistance; Cells; Tumorigenesis; Progression; Activation; Invasion
Sprache englisch
Veröffentlichungsjahr 2019
HGF-Berichtsjahr 2019
ISSN (print) / ISBN 0143-3334
e-ISSN 1460-2180
Zeitschrift Carcinogenesis
Quellenangaben Band: 41, Heft: 8, Seiten: 1134-1144 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Lung Research
PSP-Element(e) G-501600-003
G-501600-001
Förderungen REPSIRE2 European Respiratory Society Fellowship
Greek national funds through an action entitled "Reinforcement of Postdoctoral Researchers" (NSRF 2014 -2020)
Greek State Scholarship Foundation (IKY) programme - European Union (European Social Fund-ESF)
European Research Council
Hellenic Thoracic Society
DOI 10.1093/carcin/bgz190
WOS ID WOS:000577167900013
PubMed ID 31740923
Erfassungsdatum 2019-11-28
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