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

Cell Rep. 2021 Mar 2;34(9):108800. doi: 10.1016/j.celrep.2021.108800.

Abstract

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.

Keywords: ILK; PAK1; Rac3; endothelin A receptor; endothelin-1; invadopodia; mesothelial cells; serous ovarian cancer; β-arr1; βPIX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / genetics
  • Actin Depolymerizing Factors / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Coculture Techniques
  • Databases, Genetic
  • Endothelin A Receptor Antagonists / pharmacology
  • Endothelin-1 / pharmacology*
  • Epithelial Cells / enzymology*
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Peritoneum / enzymology*
  • Peritoneum / pathology
  • Phenylpropionates / pharmacology
  • Phosphorylation
  • Podosomes / drug effects*
  • Podosomes / enzymology
  • Podosomes / genetics
  • Podosomes / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Pyridazines / pharmacology
  • Receptor, Endothelin A / drug effects
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin A / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Signal Transduction
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays
  • beta-Arrestin 1 / genetics
  • beta-Arrestin 1 / metabolism
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism

Substances

  • ARHGEF7 protein, human
  • ARRB1 protein, human
  • Actin Depolymerizing Factors
  • Antineoplastic Agents
  • EDNRA protein, human
  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • Phenylpropionates
  • Pyridazines
  • RAC3 protein, human
  • Receptor, Endothelin A
  • Rho Guanine Nucleotide Exchange Factors
  • beta-Arrestin 1
  • integrin-linked kinase
  • PAK1 protein, human
  • Protein Serine-Threonine Kinases
  • p21-Activated Kinases
  • rac GTP-Binding Proteins
  • ambrisentan