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

Caroline Volz; Sara Breid; Carolin Selenz; Alina Zaplatina; Kristina Golfmann; Lydia Meder; Felix Dietlein; Sven Borchmann; Sampurna Chatterjee; Maike Siobal; Jakob Schöttle; Alexandra Florin; Mirjam Koker; Marieke Nill; Luka Ozretić; Niklas Uhlenbrock; Steven Smith; Reinhard Büttner; Hui Miao; Bingcheng Wang; H Christian Reinhardt; Daniel Rauh; Michael Hallek; Amparo Acker-Palmer; Lukas C Heukamp; Roland T Ullrich

doi:10.1016/j.celrep.2020.107568

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

Cell Rep. 2020 Apr 28;31(4):107568. doi: 10.1016/j.celrep.2020.107568.

Authors

Caroline Volz¹, Sara Breid¹, Carolin Selenz¹, Alina Zaplatina¹, Kristina Golfmann¹, Lydia Meder¹, Felix Dietlein², Sven Borchmann³, Sampurna Chatterjee⁴, Maike Siobal⁴, Jakob Schöttle⁵, Alexandra Florin⁶, Mirjam Koker¹, Marieke Nill¹, Luka Ozretić⁷, Niklas Uhlenbrock⁸, Steven Smith⁸, Reinhard Büttner⁶, Hui Miao⁹, Bingcheng Wang⁹, H Christian Reinhardt¹, Daniel Rauh⁸, Michael Hallek⁴, Amparo Acker-Palmer¹⁰, Lukas C Heukamp¹¹, Roland T Ullrich¹²

Affiliations

¹ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.
² 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.
³ 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.
⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
⁵ 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.
⁶ Institute of Pathology, University Hospital Medical School, Cologne, Germany.
⁷ Department of Cellular Pathology, Royal Free Hospital, London NW3 2QG, UK.
⁸ Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
⁹ 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.
¹⁰ Institute for Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.
¹¹ Institute for Hematopathology Hamburg, Hamburg, Germany.
¹² 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.

PMID: 32348765
DOI: 10.1016/j.celrep.2020.107568

Abstract

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.

Keywords: NSCLC; RSK; S897 EphA2; VEGFR2 inhibition; tumor cell invasion.

Publication types

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

MeSH terms

Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism*
Carcinoma, Non-Small-Cell Lung / pathology
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
Neoplasm Invasiveness
Neoplasm Metastasis
Receptor, EphA2 / metabolism*
Serine / metabolism*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / genetics
Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

Serine
Receptor, EphA2
Vascular Endothelial Growth Factor Receptor-2