HMENA is a key regulator in endothelin-1/β-arrestin1- induced invadopodial function and metastatic process

Francesca Di Modugno, Valentina Caprara, Lidia Chellini, Piera Tocci, Francesca Spadaro, Gabriella Ferrandina, Andrea Sacconi, Giovanni Blandino, Paola Nisticò, Anna Bagnato, Laura Rosanò

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENAδv6 isoforms through β-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of β-arr1 with hMENA/hMENAδv6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of β-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/β-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENAδv6 for ET-1/ β-arr1-induced invadopodial activity and ovarian cancer progression.

Original languageEnglish
Pages (from-to)3132-3137
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number12
DOIs
Publication statusPublished - Mar 20 2018

Fingerprint

Endothelin-1
Endothelin A Receptors
Ovarian Neoplasms
Cortactin
Transendothelial and Transepithelial Migration
Metalloproteases
Transcriptome
Heterografts
Actins
Neoplasms
Protein Isoforms
Up-Regulation
Membranes

Keywords

  • Endothelin receptor
  • HMENA
  • Invadopodia
  • Ovarian cancer
  • β-arrestin

ASJC Scopus subject areas

  • General

Cite this

HMENA is a key regulator in endothelin-1/β-arrestin1- induced invadopodial function and metastatic process. / Di Modugno, Francesca; Caprara, Valentina; Chellini, Lidia; Tocci, Piera; Spadaro, Francesca; Ferrandina, Gabriella; Sacconi, Andrea; Blandino, Giovanni; Nisticò, Paola; Bagnato, Anna; Rosanò, Laura.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 12, 20.03.2018, p. 3132-3137.

Research output: Contribution to journalArticle

Di Modugno, Francesca ; Caprara, Valentina ; Chellini, Lidia ; Tocci, Piera ; Spadaro, Francesca ; Ferrandina, Gabriella ; Sacconi, Andrea ; Blandino, Giovanni ; Nisticò, Paola ; Bagnato, Anna ; Rosanò, Laura. / HMENA is a key regulator in endothelin-1/β-arrestin1- induced invadopodial function and metastatic process. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 12. pp. 3132-3137.
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AU - Di Modugno, Francesca

AU - Caprara, Valentina

AU - Chellini, Lidia

AU - Tocci, Piera

AU - Spadaro, Francesca

AU - Ferrandina, Gabriella

AU - Sacconi, Andrea

AU - Blandino, Giovanni

AU - Nisticò, Paola

AU - Bagnato, Anna

AU - Rosanò, Laura

PY - 2018/3/20

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N2 - Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENAδv6 isoforms through β-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of β-arr1 with hMENA/hMENAδv6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of β-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/β-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENAδv6 for ET-1/ β-arr1-induced invadopodial activity and ovarian cancer progression.

AB - Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENAδv6 isoforms through β-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of β-arr1 with hMENA/hMENAδv6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of β-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/β-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENAδv6 for ET-1/ β-arr1-induced invadopodial activity and ovarian cancer progression.

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KW - Ovarian cancer

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