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

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

Research output: Contribution to journalArticle

15 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
DOIs
Publication statusPublished - 2018

Keywords

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

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