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

Autor: Del Rio D; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy., Masi I; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy., Caprara V; Unit of Preclinical Models and New Therapeutic Agents, IRCCS-Regina Elena National Cancer Institute, Rome, 00144, Italy., Ottavi F; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy., Albertini Petroni G; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy., Salvati E; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy., Trisciuoglio D; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy., Giannitelli SM; Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico di Roma, Rome, 00128, Italy., Bagnato A; Unit of Preclinical Models and New Therapeutic Agents, IRCCS-Regina Elena National Cancer Institute, Rome, 00144, Italy., Mauri E; Department of Chemistry Materials and Chemical Engineering, University Politecnico di Milano, 20133, Milano, Italy., Spadaro F; Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Rome, 00161, Italy., Rosanò L; Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy. laura.rosano@cnr.it.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 May 22; Vol. 15 (5), pp. 358. Date of Electronic Publication: 2024 May 22.
DOI: 10.1038/s41419-024-06730-6
Abstrakt: 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 (ET A ) and B (ET B ) 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/ET A/B R/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 ET A/B R or β-arr1 silencing prevents CAF activation, invadosome function, mesothelial clearance, and the invasive ability of heterotypic spheroids. In vivo, therapeutic inhibition of ET A/B R 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 ET A/B R antagonists.
(© 2024. The Author(s).)
Databáze: MEDLINE
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