Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK

Ilenia Masi, Valentina Caprara, Francesca Spadaro, Lidia Chellini, Rosanna Sestito, Andrea Zancla, Alberto Rainer, Anna Bagnato, Laura Rosanò

Research output: Contribution to journalArticlepeer-review


Cancer cells use actin-based membrane protrusions, invadopodia, to degrade stroma and invade. In serous ovarian cancer (SOC), the endothelin A receptor (ETAR) drives invadopodia by a not fully explored coordinated function of β-arrestin1 (β-arr1). Here, we report that β-arr1 links the integrin-linked kinase (ILK)/βPIX complex to activate Rac3 GTPase, acting as a central node in the adhesion-based extracellular matrix (ECM) sensing and degradation. Downstream, Rac3 phosphorylates PAK1 and cofilin and promotes invadopodium-dependent ECM proteolysis and invasion. Furthermore, ETAR/ILK/Rac3 signaling supports the communication between cancer and mesothelial cells, favoring SOC cell adhesion and transmigration. In vivo, ambrisentan, an ETAR antagonist, inhibits the adhesion and spreading of tumor cells to intraperitoneal organs, and invadopodium marker expression. As prognostic factors, high EDNRA/ILK expression correlates with poor SOC clinical outcome. These findings provide a framework for the ET-1R/β-arr1 pathway as an integrator of ILK/Rac3-dependent adhesive and proteolytic signaling to invadopodia, favoring cancer/stroma interactions and metastatic behavior. Unraveling mechanisms governing cancer spread are an unmet need in cancer therapeutics. Masi et al. uncover an integrin linked kinase as an interactor of endothelin A receptor/β-arr1 in the establishment of ovarian cancer-stroma interactions and in directing invadopodia-mediated invasion.

Original languageEnglish
Article number108800
JournalCell Reports
Issue number9
Publication statusPublished - Mar 2 2021


  • endothelin A receptor
  • endothelin-1
  • ILK
  • invadopodia
  • mesothelial cells
  • PAK1
  • Rac3
  • serous ovarian cancer
  • β-arr1
  • βPIX

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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