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Jin Chen - One of the best experts on this subject based on the ideXlab platform.

  • host deficiency in Ephrin A1 inhibits breast cancer metastasis
    2020
    Co-Authors: Eileen Shiuan, Jin Chen, Ashwin Inala, Shan Wang, Wenqiang Song, Victoria Youngblood, Dana M Brantleysieders
    Abstract:

    Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how Ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of Ephrin-A1 wild-type ( EfnA1 +/+ ), heterozygous ( EfnA1 +/- ), or knockout ( EfnA1 -/- ) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between EfnA1 +/+ , EfnA1 +/- , and EfnA1 -/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. EfnA1 -/- mice had reduced lung colonization of 4T1 cells compared to EfnA1 +/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in EfnA1 -/- mice had reduced proliferation compared to those in EfnA1 +/+ controls. Conclusions: Our studies demonstrate that host deficiency of Ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host Ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

  • the Ephrin A1 epha2 signaling axis regulates glutamine metabolism in her2 positive breast cancer
    2016
    Co-Authors: Victoria Youngblood, Yoonha Hwang, Dana M Brantleysieders, Laura C Kim, Deanna N Edwards, Pranav R Santapuram, Steven M Stirdivant, Jin Chen
    Abstract:

    Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2(+) subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, Ephrin-A1. We demonstrate that Ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of Ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both Ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of Ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of Ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/Ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825-36. ©2016 AACR.

  • cooperative signaling between slit2 and Ephrin A1 regulates a balance between angiogenesis and angiostasis
    2011
    Co-Authors: Charlene M Dunaway, Yoonha Hwang, Jin Chen, Craig W Lindsley, Rebecca S Cook, Mark Boothby, Dana M Brantleysieders
    Abstract:

    Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro- and antiangiogenic activity. We report here that cooperation between Slit2 and Ephrin-A1 regulates a balance between the pro- and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of Ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of Ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of Ephrin-A1, providing a plausible mechanism for the pro- versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms.

  • regulation of heart valve morphogenesis by eph receptor ligand Ephrin A1
    2010
    Co-Authors: Leslie Frieden, Todd A Townsend, David B Vaught, Daniel M Delaughter, Yoonha Hwang, Joey V Barnett, Jin Chen
    Abstract:

    Disease or malformation of heart valves is one of the leading causes of morbidity and mortality in both children and adults. These congenital anomalies can remain undetected until cardiac function is compromised, making it important to understand the underlying nature of these disorders. Here we show that Ephrin-A1, a ligand for class A Eph receptor tyrosine kinases, regulates cardiac valve formation. Exogenous Ephrin-A1-Fc or overexpression of Ephrin-A1 in the heart inhibits epithelial-to-mesenchymal transformation (EMT) in chick atrioventricular cushion explants. In contrast, overexpression of wild-type EphA3 receptor promotes EMT via a kinase-dependent mechanism. To analyze Ephrin-A1 in vivo, we generated an Ephrin-A1 knockout mouse through gene targeting. Ephrin-A1 null animals are viable but exhibit impaired cardiac function. Loss of Ephrin-A1 results in thickened aortic and mitral valves in newborn and adult animals. Analysis of early embryonic hearts revealed increased cellularity in outflow tract endocardial cushions and elevated mesenchymal marker expression, suggesting that excessive numbers of cells undergo EMT. Taken together, these data indicate that Ephrin-A1 regulates cardiac valve development, making Ephrin-A1-deficient mice a novel model for congenital heart defects.

  • Ephrin A1 facilitates mammary tumor metastasis through an angiogenesis dependent mechanism mediated by epha receptor and vascular endothelial growth factor in mice
    2006
    Co-Authors: Dana M Brantleysieders, Yoonha Hwang, Wei Bin Fang, Donna J Hicks, Jin Chen
    Abstract:

    Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, Ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro , and s.c. vascular remodeling in vivo . Based on these data, we hypothesized that native, membrane-bound Ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA–mediated Ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo . Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo . Conversely, overexpression of Ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of Ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which Ephrin-A1 regulates angiogenesis. Furthermore, Ephrin-A1 knockdown diminished, whereas overexpression of Ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell–conditioned medium, suggesting that Ephrin-A1–mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered Ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that Ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread. (Cancer Res 2006; 66(21): 10315-24)

Dana M Brantleysieders - One of the best experts on this subject based on the ideXlab platform.

  • host deficiency in Ephrin A1 inhibits breast cancer metastasis
    2020
    Co-Authors: Eileen Shiuan, Jin Chen, Ashwin Inala, Shan Wang, Wenqiang Song, Victoria Youngblood, Dana M Brantleysieders
    Abstract:

    Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how Ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of Ephrin-A1 wild-type ( EfnA1 +/+ ), heterozygous ( EfnA1 +/- ), or knockout ( EfnA1 -/- ) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between EfnA1 +/+ , EfnA1 +/- , and EfnA1 -/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. EfnA1 -/- mice had reduced lung colonization of 4T1 cells compared to EfnA1 +/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in EfnA1 -/- mice had reduced proliferation compared to those in EfnA1 +/+ controls. Conclusions: Our studies demonstrate that host deficiency of Ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host Ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

  • the Ephrin A1 epha2 signaling axis regulates glutamine metabolism in her2 positive breast cancer
    2016
    Co-Authors: Victoria Youngblood, Yoonha Hwang, Dana M Brantleysieders, Laura C Kim, Deanna N Edwards, Pranav R Santapuram, Steven M Stirdivant, Jin Chen
    Abstract:

    Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2(+) subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, Ephrin-A1. We demonstrate that Ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of Ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both Ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of Ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of Ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/Ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825-36. ©2016 AACR.

  • cooperative signaling between slit2 and Ephrin A1 regulates a balance between angiogenesis and angiostasis
    2011
    Co-Authors: Charlene M Dunaway, Yoonha Hwang, Jin Chen, Craig W Lindsley, Rebecca S Cook, Mark Boothby, Dana M Brantleysieders
    Abstract:

    Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro- and antiangiogenic activity. We report here that cooperation between Slit2 and Ephrin-A1 regulates a balance between the pro- and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of Ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of Ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of Ephrin-A1, providing a plausible mechanism for the pro- versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms.

  • Ephrin A1 facilitates mammary tumor metastasis through an angiogenesis dependent mechanism mediated by epha receptor and vascular endothelial growth factor in mice
    2006
    Co-Authors: Dana M Brantleysieders, Yoonha Hwang, Wei Bin Fang, Donna J Hicks, Jin Chen
    Abstract:

    Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, Ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro , and s.c. vascular remodeling in vivo . Based on these data, we hypothesized that native, membrane-bound Ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA–mediated Ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo . Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo . Conversely, overexpression of Ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of Ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which Ephrin-A1 regulates angiogenesis. Furthermore, Ephrin-A1 knockdown diminished, whereas overexpression of Ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell–conditioned medium, suggesting that Ephrin-A1–mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered Ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that Ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread. (Cancer Res 2006; 66(21): 10315-24)

  • Ephrin A1 facilitates mammary tumor metastasis through an angiogenesis dependent mechanism mediated by epha receptor and vascular endothelial growth factor in mice
    2006
    Co-Authors: Dana M Brantleysieders, Yoonha Hwang, Wei Bin Fang, Donna J Hicks, Jin Chen
    Abstract:

    Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, Ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro, and s.c. vascular remodeling in vivo. Based on these data, we hypothesized that native, membrane-bound Ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA-mediated Ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo. Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo. Conversely, overexpression of Ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of Ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which Ephrin-A1 regulates angiogenesis. Furthermore, Ephrin-A1 knockdown diminished, whereas overexpression of Ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell-conditioned medium, suggesting that Ephrin-A1-mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered Ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that Ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread.

Yoonha Hwang - One of the best experts on this subject based on the ideXlab platform.

  • the Ephrin A1 epha2 signaling axis regulates glutamine metabolism in her2 positive breast cancer
    2016
    Co-Authors: Victoria Youngblood, Yoonha Hwang, Dana M Brantleysieders, Laura C Kim, Deanna N Edwards, Pranav R Santapuram, Steven M Stirdivant, Jin Chen
    Abstract:

    Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2(+) subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, Ephrin-A1. We demonstrate that Ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of Ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both Ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of Ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of Ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/Ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825-36. ©2016 AACR.

  • cooperative signaling between slit2 and Ephrin A1 regulates a balance between angiogenesis and angiostasis
    2011
    Co-Authors: Charlene M Dunaway, Yoonha Hwang, Jin Chen, Craig W Lindsley, Rebecca S Cook, Mark Boothby, Dana M Brantleysieders
    Abstract:

    Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro- and antiangiogenic activity. We report here that cooperation between Slit2 and Ephrin-A1 regulates a balance between the pro- and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of Ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of Ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of Ephrin-A1, providing a plausible mechanism for the pro- versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms.

  • regulation of heart valve morphogenesis by eph receptor ligand Ephrin A1
    2010
    Co-Authors: Leslie Frieden, Todd A Townsend, David B Vaught, Daniel M Delaughter, Yoonha Hwang, Joey V Barnett, Jin Chen
    Abstract:

    Disease or malformation of heart valves is one of the leading causes of morbidity and mortality in both children and adults. These congenital anomalies can remain undetected until cardiac function is compromised, making it important to understand the underlying nature of these disorders. Here we show that Ephrin-A1, a ligand for class A Eph receptor tyrosine kinases, regulates cardiac valve formation. Exogenous Ephrin-A1-Fc or overexpression of Ephrin-A1 in the heart inhibits epithelial-to-mesenchymal transformation (EMT) in chick atrioventricular cushion explants. In contrast, overexpression of wild-type EphA3 receptor promotes EMT via a kinase-dependent mechanism. To analyze Ephrin-A1 in vivo, we generated an Ephrin-A1 knockout mouse through gene targeting. Ephrin-A1 null animals are viable but exhibit impaired cardiac function. Loss of Ephrin-A1 results in thickened aortic and mitral valves in newborn and adult animals. Analysis of early embryonic hearts revealed increased cellularity in outflow tract endocardial cushions and elevated mesenchymal marker expression, suggesting that excessive numbers of cells undergo EMT. Taken together, these data indicate that Ephrin-A1 regulates cardiac valve development, making Ephrin-A1-deficient mice a novel model for congenital heart defects.

  • Ephrin A1 facilitates mammary tumor metastasis through an angiogenesis dependent mechanism mediated by epha receptor and vascular endothelial growth factor in mice
    2006
    Co-Authors: Dana M Brantleysieders, Yoonha Hwang, Wei Bin Fang, Donna J Hicks, Jin Chen
    Abstract:

    Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, Ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro , and s.c. vascular remodeling in vivo . Based on these data, we hypothesized that native, membrane-bound Ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA–mediated Ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo . Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo . Conversely, overexpression of Ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of Ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which Ephrin-A1 regulates angiogenesis. Furthermore, Ephrin-A1 knockdown diminished, whereas overexpression of Ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell–conditioned medium, suggesting that Ephrin-A1–mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered Ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that Ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread. (Cancer Res 2006; 66(21): 10315-24)

  • Ephrin A1 facilitates mammary tumor metastasis through an angiogenesis dependent mechanism mediated by epha receptor and vascular endothelial growth factor in mice
    2006
    Co-Authors: Dana M Brantleysieders, Yoonha Hwang, Wei Bin Fang, Donna J Hicks, Jin Chen
    Abstract:

    Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, Ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro, and s.c. vascular remodeling in vivo. Based on these data, we hypothesized that native, membrane-bound Ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA-mediated Ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo. Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo. Conversely, overexpression of Ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of Ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which Ephrin-A1 regulates angiogenesis. Furthermore, Ephrin-A1 knockdown diminished, whereas overexpression of Ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell-conditioned medium, suggesting that Ephrin-A1-mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered Ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that Ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread.

Spiro Getsios - One of the best experts on this subject based on the ideXlab platform.

  • epha2 transmembrane domain is uniquely required for keratinocyte migration by regulating Ephrin A1 levels
    2018
    Co-Authors: Rosa Ventrella, Nihal Kaplan, Robert M Lavker, Paul Hoover, Bethany Perez E White, Spiro Getsios
    Abstract:

    EphA2 receptor tyrosine kinase is activated by Ephrin-A1 ligand, which harbors a glycosylphosphatidylinositol anchor that enhances lipid raft localization. Although EphA2 and Ephrin-A1 modulate keratinocyte migration and differentiation, the ability of this cell-cell communication complex to localize to different membrane regions in keratinocytes remains unknown. Using a combination of biochemical and imaging approaches, we provide evidence that Ephrin-A1 and a ligand-activated form of EphA2 partition outside of lipid raft domains in response to calcium-mediated cell-cell contact stabilization in normal human epidermal keratinocytes. EphA2 transmembrane domain swapping with a shorter and molecularly distinct transmembrane domain of EphA1 resulted in decreased localization of this receptor tyrosine kinase at cell-cell junctions and increased expression of Ephrin-A1, which is a negative regulator of keratinocyte migration. Accordingly, altered EphA2 membrane distribution at cell-cell contacts limited the ability of keratinocytes to seal linear scratch wounds in vitro in an Ephrin-A1–dependent manner. Collectively, these studies highlight a key role for the EphA2 transmembrane domain in receptor-ligand membrane distribution at cell-cell contacts that modulates Ephrin-A1 levels to allow for efficient keratinocyte migration with relevance for cutaneous wound healing.

  • epha2 Ephrin A1 mediate corneal epithelial cell compartmentalization via adam10 regulation of egfr signaling
    2018
    Co-Authors: Nihal Kaplan, Han Peng, Robert M Lavker, Rosa Ventrella, Sonali Palghosh, Constadina Arvanitis, Joshua Z Rappoport, Brian J Mitchell, Mary Ann Stepp, Spiro Getsios
    Abstract:

    Purpose Progenitor cells of the limbal epithelium reside in a discrete area peripheral to the more differentiated corneal epithelium and maintain tissue homeostasis. What regulates the limbal-corneal epithelial boundary is a major unanswered question. Ephrin-A1 ligand is enriched in the limbal epithelium, whereas EphA2 receptor is concentrated in the corneal epithelium. This reciprocal pattern led us to assess the role of Ephrin-A1 and EphA2 in limbal-corneal epithelial boundary organization. Methods EphA2-expressing corneal epithelial cells engineered to express Ephrin-A1 were used to study boundary formation in vitro in a manner that mimicked the relative abundance of these juxtamembrane signaling proteins in the limbal and corneal epithelium in vivo. Interaction of these two distinct cell populations following initial seeding into discrete culture compartments was assessed by live cell imaging. Immunofluoresence and immunoblotting was used to evaluate the contribution of downstream growth factor signaling and cell-cell adhesion systems to boundary formation at sites of heterotypic contact between Ephrin-A1 and EphA2 expressing cells. Results Ephrin-A1-expressing cells impeded and reversed the migration of EphA2-expressing corneal epithelial cells upon heterotypic contact formation leading to coordinated migration of the two cell populations in the direction of an Ephrin-A1-expressing leading front. Genetic silencing and pharmacologic inhibitor studies demonstrated that the ability of Ephrin-A1 to direct migration of EphA2-expressing cells depended on an a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and epidermal growth factor receptor (EGFR) signaling pathway that limited E-cadherin-mediated adhesion at heterotypic boundaries. Conclusions Ephrin-A1/EphA2 signaling complexes play a key role in limbal-corneal epithelial compartmentalization and the response of these tissues to injury.

  • epha2 Ephrin A1 signaling complexes restrict corneal epithelial cell migration
    2012
    Co-Authors: Nihal Kaplan, Anees Fatima, Han Peng, Paul Bryar, Robert M Lavker, Spiro Getsios
    Abstract:

    PURPOSE. Eph/Ephrin signaling proteins are present in the corneal epithelium, where their function remains unknown. The authors examined the role of the EphA2 receptor and Ephrin-A1 ligand in human corneal epithelial cell migration. METHODS. Immunohistochemical analysis of EphA2 and Ephrin-A1 in healthy and diabetic corneas was performed in concert with linear scratch wound healing studies in primary and telomerase-immortalized human corneal epithelial cells. Corneal epithelial cells were exposed to a soluble Ephrin-A1-Fc peptide mimetic that targets EphA2 to trigger receptor phosphorylation and subsequent downregulation. Genetic modulation of EphA2 and Ephrin-A1 levels was combined with manipulation of Erk1/2 or Akt signaling during wound healing. RESULTS. EphA2 was immunolocalized to human corneal epithelial cells in vivo and in vitro. Ephrin-A1 ligand targeting of EphA2 restricted the ability of corneal epithelial cells to seal linear scratch wounds in a manner that was associated with a transient reduction in Erk1/2 and Akt activation state. EphrinA1-Fc treatment delayed wound healing independently of MekErk1/2 signaling but was no longer capable of restricting migration after pharmacologic blockade of the PI3K-Akt pathway. Interestingly, Ephrin-A1 immunoreactivity was increased in the corneal epithelia of diabetic individuals, mice maintained on a high-fat diet, or cultured corneal epithelial cells exposed to high glucose, which exhibit impaired Akt signaling and slower wound healing responses. CONCLUSIONS. EphA2 attenuates corneal epithelial cell migration when stimulated by Ephrin-A1 ligand in a manner that involves the suppression of Akt. Elevated levels of Ephrin-A1 may contribute to diabetic keratopathies by persistently engaging EphA2 and prohibiting Akt-dependent corneal epithelial repair processes. (Invest Ophthalmol Vis Sci. 2012;53:936 –945) DOI:

  • Ligand Targeting of EphA2 Enhances Keratinocyte Adhesion and Differentiation via Desmoglein 1
    2010
    Co-Authors: Samantha Lin, K. Gordon, Nihal Kaplan, Spiro Getsios
    Abstract:

    EphA2 is a receptor tyrosine kinase that is engaged and activated by membrane-linked Ephrin-A ligands residing on adjacent cell surfaces. Ligand targeting of EphA2 has been implicated in epithelial growth regulation by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2)-mitogen activated protein kinase (MAPK) pathway. Although contact-dependent EphA2 activation was required for dampening Erk1/2-MAPK signaling after a calcium switch in primary human epidermal keratinocytes, the loss of this receptor did not prevent exit from the cell cycle. Incubating keratinocytes with a soluble Ephrin-A1-Fc peptide mimetic to target EphA2 further increased receptor activation leading to its down-regulation. Moreover, soluble ligand targeting of EphA2 restricted the lateral expansion of epidermal cell colonies without limiting proliferation in these primary cultures. Rather, Ephrin-A1-Fc peptide treatment promoted epidermal cell colony compaction and stratification in a manner that was associated with increased keratinocyte differentiation. The ligand-dependent increase in keratinocyte adhesion and differentiation relied largely upon the up-regulation of desmoglein 1, a desmosomal cadherin that maintains the integrity and differentiated state of suprabasal keratinocytes in the epidermis. These data suggest that keratinocytes expressing EphA2 in the basal layer may respond to Ephrin-A1–based cues from their neighbors to facilitate entry into a terminal differentiation pathway.

Yoshiro Maru - One of the best experts on this subject based on the ideXlab platform.

  • roles of ephA1 a2 and Ephrin A1 in cancer
    2019
    Co-Authors: Katsuaki Ieguchi, Yoshiro Maru
    Abstract:

    The biological functions of the Eph/Ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/Ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/Ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and Ephrin are up- or down-regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy. The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin-A1 that is a membrane-anchored ligand for EphAs was co-localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of Ephrin-A1-induced lung metastasis by understanding the physiological function of Ephrin-A1 in lungs. This review focuses on the function of EphA1, EphA2, and Ephrin-A1 in tumors and an establishment of pre-metastatic microenvironment in the lungs.

  • Ephrin A1 expression induced by s100a8 is mediated by the toll like receptor 4
    2013
    Co-Authors: Katsuaki Ieguchi, Takeshi Tomita, Tsutomu Omori, Akiko Komatsu, Atsuko Deguchi, Yoshiro Maru
    Abstract:

    The deregulation of Eph/Ephrin protein expression has been shown to lead to tumor development and progression. Both mRNA and protein expression analyses using clinical samples have demonstrated that Ephrin-A1 is over-expressed in various cancers and positively correlates with a poor prognosis for cancer patients. The prognosis of cancer patients depends on metastasis to distant organs. We previously demonstrated that ADAM12 metalloproteinase cleaved Ephrin-A1 and ADAM12-cleaved Ephrin-A1 enhanced vascular permeability by degrading VE-cadherin and the EphA2 receptor at the plasma membrane. An increase of soluble Ephrin-A1 levels in the serum facilitated tumor cell recruitment to the lungs, which resulted in lung metastasis. We also found that Ephrin-A1 was overexpressed in 3LL tumors, a highly metastatic tumor, in mice and TNFα, an authentic positive regulator of Ephrin-A1, was not elevated in the tumors, whereas S100A8 was. Moreover, S100A8 induced Ephrin-A1 expression mediated by the toll-like receptor 4 (TLR4). S100A8 is known to be an endogenous ligand for TLR4 and its expression was shown to be increased in the lungs at the premetastatic phase. Thus, S100A8 and Ephrin-A1 contribute to lung metastasis. Therefore, elucidating the regulation mechanism of Ephrin-A1 overexpression is of importance and may lead to the development of therapeutic drugs against tumor growth and metastasis.

  • ADAM12-cleaved Ephrin-A1 contributes to lung metastasis
    2013
    Co-Authors: Katsuaki Ieguchi, Takeshi Tomita, Tsutomu Omori, Akiko Komatsu, Atsuko Deguchi, Junko Masuda, S. L. Duffy, Malcolm G. Coulthard, Andrew W. Boyd, Yoshiro Maru
    Abstract:

    Eph receptor tyrosine kinases and their Ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of Ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/Ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/Ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and Ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced Ephrin-A1 cleavage in response to transforming growth factor-β1 in primary tumors. Released soluble Ephrin-A1 in the serum deteriorated the EphA1/Ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble Ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis.

  • ephA1 interacts with integrin linked kinase and regulates cell morphology and motility
    2009
    Co-Authors: Tohru Yamazaki, Tsutomu Omori, Junko Masuda, Ryosuke Usui, Hitomi Akiyama, Yoshiro Maru
    Abstract:

    The Eph-Ephrin receptor-ligand system is implicated in cell behavior and morphology. EphA1 is the founding member of the Eph receptors, but little is known about its function. Here, we show that activation of EphA1 kinase inhibits cell spreading and migration in a RhoA-ROCK-dependent manner. We also describe a novel interaction between EphA1 and integrin-linked kinase (ILK), a mediator of interactions between integrin and the actin cytoskeleton. The C-terminal sterile alpha motif (SAM) domain of EphA1 is required and the ankyrin region of ILK is sufficient for the interaction between EphA1 and ILK. The interaction is independent of EphA1 kinase activity but dependent on stimulation of the EphA1 ligand Ephrin-A1. Activation of EphA1 kinase resulted in a decrease of ILK activity. Finally, we demonstrated that expression of a kinase-active form of ILK (S343D) rescued the EphA1-mediated spreading defect, and attenuated RhoA activation. These results suggest that EphA1 regulates cell morphology and motility through the ILK-RhoA-ROCK pathway.