Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC.

Carcinoma, Non-Small-Cell Lung / genetics Humans Lung Neoplasms / genetics Neoplasm Invasiveness Neoplasm Metastasis Receptor, EphA2 / metabolism Serine / metabolism Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
NSCLC RSK S897 EphA2 VEGFR2 inhibition tumor cell invasion

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
28 04 2020
Historique:
received: 04 04 2019
revised: 11 03 2020
accepted: 03 04 2020
entrez: 30 4 2020
pubmed: 30 4 2020
medline: 14 5 2021
Statut: ppublish

Résumé

Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in ∼20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2. Inhibition of RSK decreases phosphorylation of Serine 897 EphA2. Selective genetic modeling of Serine 897 of EphA2 or inhibition of EphA2 abrogates the formation of metastases in vivo upon VEGFR2 inhibition. In summary, these findings demonstrate that VEGFR2-targeted therapy conditions VEGFR2-positive NSCLC to Serine 897 EphA2-dependent aggressive tumor growth and metastasis. These data shed light on the molecular mechanisms explaining the limited efficacy of VEGFR2-targeted anti-angiogenic treatment in lung cancer patients.

Identifiants

DOI: 10.1016/j.celrep.2020.107568 PMID: 32348765
pubmed: 32348765
pii: S2211-1247(20)30517-9
doi: 10.1016/j.celrep.2020.107568
pii:
doi:

Substances chimiques

Serine 452VLY9402
Receptor, EphA2 EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-2 EC 2.7.10.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

107568

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

Auteurs

Caroline Volz (C)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Sara Breid (S)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Carolin Selenz (C)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Alina Zaplatina (A)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Kristina Golfmann (K)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Lydia Meder (L)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Felix Dietlein (F)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, US Institute for Pathology, Cambridge, MA, USA.

Sven Borchmann (S)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany; University of Cologne, Department I of Internal Medicine, German Hodgkin Study Group (GHSG), Cologne, Germany; University of Cologne, Department I of Internal Medicine, Else Kröner Forschungskolleg Clonal Evolution in Cancer, Cologne, Germany.

Sampurna Chatterjee (S)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.

Maike Siobal (M)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.

Jakob Schöttle (J)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Department of Translational Genomics, University of Cologne, Medical Faculty, Cologne, Germany.

Alexandra Florin (A)

Institute of Pathology, University Hospital Medical School, Cologne, Germany.

Mirjam Koker (M)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Marieke Nill (M)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Luka Ozretić (L)

Department of Cellular Pathology, Royal Free Hospital, London NW3 2QG, UK.

Niklas Uhlenbrock (N)

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.

Steven Smith (S)

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.

Reinhard Büttner (R)

Institute of Pathology, University Hospital Medical School, Cologne, Germany.

Hui Miao (H)

Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pharmacology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Bingcheng Wang (B)

Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pharmacology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

H Christian Reinhardt (HC)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.

Daniel Rauh (D)

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.

Michael Hallek (M)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.

Amparo Acker-Palmer (A)

Institute for Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.

Lukas C Heukamp (LC)

Institute for Hematopathology Hamburg, Hamburg, Germany.

Roland T Ullrich (RT)

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany. Electronic address: roland.ullrich@uk-koeln.de.

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Classifications MeSH

questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Invasion tumorale › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs à activité tyrosine kinase › Famille des récepteurs Eph › Récepteur EphA2 › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Sérine › Inhibition of Tumor VEGFR2 Induces Serine 897...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs aux facteurs de croissance endothéliale vasculaire › Récepteur-2 au facteur croissance endothéliale vasculaire › Inhibition of Tumor VEGFR2 Induces Serine 897...