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

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

doi:10.1016/j.celrep.2020.107568

Cited by 16 publications

(11 citation statements)

References 55 publications

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“…Another possibility is that EPHA2 may bind to another ROBO receptor or yet another receptor and inhibit proliferation. Concordant with this speculation, while this manuscript was being reviewed Volz et al (2020) published their study where in NSCLC EPHA2 forms heterodimers with VEGF and inhibits metastasis. However, in the cell lines with EPHA2 low and ROBO1 high SLIT2 did not inhibit cell proliferation.…”

Section: Ll Open Access Iscience Articlementioning

confidence: 69%

Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas

et al. 2020

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The tyrosine kinase receptor ephrin receptor A2 (EPHA2) is overexpressed in lung (LSCC) and head and neck (HNSCC) squamous cell carcinomas. Although EPHA2 can inhibit tumorigenesis in a ligand-dependent fashion via phosphorylation of Y588 and Y772, it can promote tumorigenesis in a ligand-independent manner via phosphorylation of S897. Here, we show that EPHA2 and Roundabout Guidance Receptor 1 (ROBO1) interact to form a functional heterodimer. Furthermore, we show that the ROBO1 ligand Slit Guidance Ligand 2 (SLIT2) and ensartinib, an inhibitor of EPHA2, can attenuate growth of HNSCC cells and act synergistically in LSCC cells. Our results suggest that patients with LSCC and HNSCC may be stratified and treated based on their EPHA2 and ROBO1 expression patterns. Although~73% of patients with LSCC could benefit from SLIT2+ensartinib treatment,~41% of patients with HNSCC could be treated with either SLIT2 or ensartinib. Thus, EPHA2 and ROBO1 represent potential LSCC and HNSCC theranostics.

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Section: Ll Open Access Iscience Articlementioning

confidence: 69%

Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas

et al. 2020

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“…Among the protein markers was CD73, also known as 5′‐NT and previously reported to act as an immune suppressor in multiple ways within the tumor microenvironment [ 25 , 26 , 27 , 28 ]. Another marker was EphA2, an oncogenic receptor tyrosine kinase linked to poor overall survival in NSCLC [ 29 , 30 , 31 ] and involved in EGFR as well as VEGFR2 signaling in NSCLC [ 32 , 33 , 34 ]. Both CD73 and EphA2 also showed a significant correlation to PD‐L1 in univariate regression analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiplex immune protein profiling of fine‐needle aspirates from patients with non‐small‐cell lung cancer reveals signatures associated with PD‐L1 expression and tumor stage

et al. 2021

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Biomarker signatures identified through minimally invasive procedures already at diagnosis of non-small-cell lung cancer (NSCLC) could help to guide treatment with immune checkpoint inhibitors (ICI). Here, we performed multiplex profiling of immune-related proteins in fine-needle aspirate (FNA) samples of thoracic lesions from patients with NSCLC to assess PD-L1 expression and identify related protein signatures. Transthoracic FNA samples from 14 patients were subjected to multiplex antibody-based profiling by proximity extension assay (PEA). PEA profiling employed protein panels relevant to immune and tumor signaling and was followed by Qlucore Ò Omics Explorer analysis. All lesions analyzed were NSCLC adenocarcinomas, and PEA profiles could be used to monitor 163 proteins in all but one sample. Multiple key immune signaling components (including CD73, granzyme A, and chemokines CCL3 and CCL23) were identified and expression of several of these proteins (e.g., CCL3 and CCL23) correlated to PD-L1 expression. We also found EphA2, a marker previously linked to inferior NSCLC prognosis, to correlate to PD-L1 expression. Our identified protein signatures related to stage included, among others, CXCL10 and IL12RB1. We conclude that transthoracic FNA allows for extensive immune and tumor protein profiling with assessment of putative biomarkers of important for ICI treatment selection in NSCLC.

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“…VEGFR-2 mediates the main physiological functions of VEGF. VEGF, the vascular permeability factor (VPF), is an essential and crucial growth factor for vascular endothelial cells, and plays various roles in cardiovascular system ( Wang et al, 2019 ), central nervous system ( Bellon et al, 2010 ; Luck et al, 2019 ), hematopoiesis ( Hooper et al, 2009 ), development ( Karaman et al, 2018 ), and tumorigenesis ( Volz et al, 2020 ; Zhong et al, 2020 ). Despite having so many physiological functions, the main physiological functions of VEGF on endothelial cells are almost all achieved by activating VEGFR-2, including stimulating endothelial cell proliferation, increasing vascular permeability, and chemotaxis to endothelial cells, etc.…”

Section: Vegfr-2 Physiological Functions and Pathological Rolesmentioning

confidence: 99%

Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

Wang

Bove²,

Simone³

et al. 2020

Front. Cell Dev. Biol.

162

141

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The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) play crucial roles in vasculogenesis and angiogenesis. Angiogenesis is an important mechanism in many physiological and pathological processes, and is involved in endothelial cell proliferation, migration, and survival, then leads to further tubulogenesis, and finally promotes formation of vessels. This series of signaling cascade pathways are precisely mediated by VEGF/VEGFR-2 system. The VEGF binding to the IgD2 and IgD3 of VEGFR-2 induces the dimerization of the receptor, subsequently the activation and trans-autophosphorylation of the tyrosine kinase, and then the initiation of the intracellular signaling cascades. Finally the VEGF-activated VEGFR-2 stimulates and mediates variety of signaling transduction, biological responses, and pathological processes in angiogenesis. Several crucial phosphorylated sites Tyr801, Try951, Try1175, and Try1214 in the VEGFR-2 intracellular domains mediate several key signaling processes including PLCγ-PKC, TSAd-Src-PI3K-Akt, SHB-FAK-paxillin, SHB-PI3K-Akt, and NCK-p38-MAPKAPK2/3 pathways. Based on the molecular structure and signaling pathways of VEGFR-2, the strategy of the VEGFR-2-targeted therapy should be considered to employ in the treatment of the VEGF/VEGFR-2-associated diseases by blocking the VEGF/VEGFR-2 signaling pathway, inhibiting VEGF and VEGFR-2 gene expression, blocking the binding of VEGF and VEGFR-2, and preventing the proliferation, migration, and survival of vascular endothelial cells expressing VEGFR-2.

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

Abstract: Highlights d VEGFR2 inhibition in VEGFR2-positive NSCLC tumor cells induces tumor cell invasion d EphA2-S897 mediates invasive phenotype induced by VEGFR2 inhibition d These data provide a mechanism for the limited efficacy of VEGFR2-targeted therapy

Cited by 16 publications

References 55 publications

Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas

Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas

Multiplex immune protein profiling of fine‐needle aspirates from patients with non‐small‐cell lung cancer reveals signatures associated with PD‐L1 expression and tumor stage

Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

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