Cell Reports (Apr 2020)
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
Affiliations
- Caroline Volz
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
- Maike Siobal
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
- Jakob Schöttle
- 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
- Institute of Pathology, University Hospital Medical School, Cologne, Germany
- Mirjam Koker
- 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
- 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
- Department of Cellular Pathology, Royal Free Hospital, London NW3 2QG, UK
- Niklas Uhlenbrock
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Steven Smith
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Reinhard Büttner
- Institute of Pathology, University Hospital Medical School, Cologne, Germany
- Hui Miao
- 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
- 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
- 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
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Michael Hallek
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
- Amparo Acker-Palmer
- Institute for Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany
- Lukas C. Heukamp
- Institute for Hematopathology Hamburg, Hamburg, Germany
- Roland T. Ullrich
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 4
Abstract
Summary: 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. : Anti-angiogenic treatment targeting VEGFR2 signaling has shown limited efficacy in lung cancer patients. Volz et al. show that VEGFR2 inhibition leads to a pro-invasive phenotype in VEGFR2-positive non-small cell lung cancer cells, which is mediated by phosphorylation of EphA2-S897. Keywords: VEGFR2 inhibition, tumor cell invasion, S897 EphA2, RSK, NSCLC
