The β-arrestin1/endothelin axis bolsters ovarian fibroblast-dependent invadosome activity and cancer cell metastatic potential

  • Cell Death Dis. 2024 May 22;15(5):358. doi: 10.1038/s41419-024-06730-6.
Danila Del Rio  #  1 ,  Ilenia Masi  #  1 ,  Valentina Caprara  2 ,  Flavia Ottavi  1 ,  Gabriele Albertini Petroni  1 ,  Erica Salvati  1 ,  Daniela Trisciuoglio  1 ,  Sara Maria Giannitelli  3 ,  Anna Bagnato  2 ,  Emanuele Mauri  4 ,  Francesca Spadaro  5 ,  Laura Rosanò  6
Affiliations
  • 1. Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy.
  • 2. Unit of Preclinical Models and New Therapeutic Agents, IRCCS-Regina Elena National Cancer Institute, Rome, 00144, Italy.
  • 3. Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico di Roma, Rome, 00128, Italy.
  • 4. Department of Chemistry Materials and Chemical Engineering, University Politecnico di Milano, 20133, Milano, Italy.
  • 5. Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Rome, 00161, Italy.
  • 6. Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy. [email protected].
  • # Contributed equally.
PMID: 38777849 DOI: 10.1038/s41419-024-06730-6
Abstract

Recruitment of fibroblasts to tumors and their activation into cancer-associated fibroblasts (CAFs) is a strategy used by tumor cells to direct extracellular matrix (ECM) remodeling, invasion, and metastasis, highlighting the need to investigate the molecular mechanisms driving CAF function. Endothelin-1 (ET-1) regulates the communication between Cancer and stroma and facilitates the progression of serous ovarian Cancer (SOC). By binding to Endothelin A (ETA) and B (ETB) receptors, ET-1 enables the recruitment of β-arrestin1 (β-arr1) and the formation of signaling complexes that coordinate tumor progression. However, how ET-1 receptors might "educate" human ovarian fibroblasts (HOFs) to produce altered ECM and promote metastasis remains to be elucidated. This study identifies ET-1 as a pivotal factor in the activation of CAFs capable of proteolytic ECM remodeling and the generation of heterotypic spheroids containing Cancer cells with a propensity to metastasize. An autocrine/paracrine ET-1/ETA/BR/β-arr1 loop enhances HOF proliferation, upregulates CAF marker expression, secretes pro-inflammatory cytokines, and increases Collagen contractility, and cell motility. Furthermore, ET-1 facilitates ECM remodeling by promoting the lytic activity of invadosome and activation of Integrin β1. In addition, ET-1 signaling supports the formation of heterotypic HOF/SOC spheroids with enhanced ability to migrate through the mesothelial monolayer, and invade, representing metastatic units. The blockade of ETA/BR or β-arr1 silencing prevents CAF activation, invadosome function, mesothelial clearance, and the invasive ability of heterotypic spheroids. In vivo, therapeutic inhibition of ETA/BR using bosentan (BOS) significantly reduces the metastatic potential of combined HOFs/SOC cells, associated with enhanced apoptotic effects on tumor cells and stromal components. These findings support a model in which ET-1/β-arr1 reinforces tumor/stroma interaction through CAF activation and fosters the survival and metastatic properties of SOC cells, which could be counteracted by ETA/BR antagonists.

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