Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas
Summary: 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-i...
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2020-11-01
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doaj-862bc629bc1841d3ab9053896facbb152020-11-25T03:56:34ZengElsevieriScience2589-00422020-11-012311101692Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell CarcinomasSaumya Srivastava0Ka Ming Pang1Mari Iida2Michael S. Nelson3Jiayi Liu4Arin Nam5Jiale Wang6Isa Mambetsariev7Raju Pillai8Atish Mohanty9Nellie McDaniel10Amita Behal11Prakash Kulkarni12Deric L. Wheeler13Ravi Salgia14Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Surgery, City of Hope National Medical Center, Duarte, CA, USADepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI 53705-2275, USALight Microscopy Core, City of Hope National Medical Center, Duarte, CA, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Pathology, City of Hope National Medical Center, Duarte, CA, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI 53705-2275, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USADepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI 53705-2275, USA; Corresponding authorDepartment of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220308841Biological SciencesCell BiologyMolecular BiologyCancer Systems Biology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Saumya Srivastava Ka Ming Pang Mari Iida Michael S. Nelson Jiayi Liu Arin Nam Jiale Wang Isa Mambetsariev Raju Pillai Atish Mohanty Nellie McDaniel Amita Behal Prakash Kulkarni Deric L. Wheeler Ravi Salgia |
spellingShingle |
Saumya Srivastava Ka Ming Pang Mari Iida Michael S. Nelson Jiayi Liu Arin Nam Jiale Wang Isa Mambetsariev Raju Pillai Atish Mohanty Nellie McDaniel Amita Behal Prakash Kulkarni Deric L. Wheeler Ravi Salgia Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas iScience Biological Sciences Cell Biology Molecular Biology Cancer Systems Biology |
author_facet |
Saumya Srivastava Ka Ming Pang Mari Iida Michael S. Nelson Jiayi Liu Arin Nam Jiale Wang Isa Mambetsariev Raju Pillai Atish Mohanty Nellie McDaniel Amita Behal Prakash Kulkarni Deric L. Wheeler Ravi Salgia |
author_sort |
Saumya Srivastava |
title |
Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas |
title_short |
Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas |
title_full |
Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas |
title_fullStr |
Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas |
title_full_unstemmed |
Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas |
title_sort |
activation of epha2-robo1 heterodimer by slit2 attenuates non-canonical signaling and proliferation in squamous cell carcinomas |
publisher |
Elsevier |
series |
iScience |
issn |
2589-0042 |
publishDate |
2020-11-01 |
description |
Summary: 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. |
topic |
Biological Sciences Cell Biology Molecular Biology Cancer Systems Biology |
url |
http://www.sciencedirect.com/science/article/pii/S2589004220308841 |
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