Dynamic integrin expression changes and adhesion-driven mitobiogenesis in ovarian cancer metastasis

Abstract

Ovarian cancer is the 6th leading cause of cancer-related deaths in women, with survival rates of only 31% in metastatic disease. The unique transcoelomic dissemination of ovarian cancer cells includes detachment from the primary site, aggregation into multicellular spheroids, and attachment and invasion of distant tissues. Successful peritoneal metastasis requires cancer cells to adapt to a changing microenvironment, which necessitates coordinated changes in cell adhesion, ligand regulators, and mitochondrial function. Prior studies have demonstrated that aggregation promotes survival by fragmenting mitochondria and reducing metabolic activity, which is reversed by mitobiogenesis, high metabolic activity, and proliferation after adhesion to secondary sites. Here, we investigated the role of integrin-mediated adhesion in regulating mitochondrial and metabolic adaptation at the secondary adhesion site during ovarian cancer dissemination. By modeling the primary adherent, aggregation (spheroid), and adherent spheroid stage under physiologically relevant oxygen and nutrient conditions, we demonstrate that integrin expression is highly dynamic throughout dissemination and is accompanied by coordinated changes of other adhesion molecules, extracellular matrix (ECM) components, and their regulators. Spatial expression analyses revealed that integrins and CD44 exhibit distinct localization patterns within spheroids and were frequently observed in the nucleus, suggesting a novel role in transcriptional regulation that may contribute to survival, cellular plasticity, and metastatic progression. Expression and functional studies identified ITGαVβ1 as key mediators of spheroid adhesion and outgrowth at secondary sites. While mitochondrial activity is suppressed during aggregation, adhesion induces metabolic reprogramming characterized by improved mitochondrial respiration through enhanced mitobiogenesis to support outgrowth and invasion for successful metastasis. This process is driven by signaling through the ITGαVβ1/FAK pathway, confirmed by the pharmacological inhibition of ITGαVβ1 or FAK, which reduced mitochondrial mass, decreased mitochondrial membrane potential, oxygen consumption rate, and inhibited or reduced spheroid outgrowth. These findings establish the ITGαVβ1/FAK axis as a central link between adhesion-mediated signaling and mitobiogenesis and are a promising therapeutic target to limit ovarian cancer metastasis and improve patient outcomes.