Year: 2025
Type: article
Abstract: Delineating the mechanisms that control the movement of cells is central to understanding diverse physiological and pathophysiological processes. The transcriptional coactivator YAP is important during development and associated with cancer metastasis. Here, we found that YAP promoted cell migration by modulating a Rho family guanosine triphosphatase (GTPase) switch involving Rac1 and RhoA, which are key regulators of cytoskeletal dynamics. YAP transcriptionally transactivated the gene encoding the Rac1 guanine nucleotide exchange factor TRIO by directly binding to its intronic enhancer. This led to the activation of Rac1 and inhibition of RhoA, which increased cell migration and invasion in vitro and in vivo. This YAP-dependent program was observed across many cell types, including human breast epithelial cells and astrocytes, but it was particularly enhanced in a patient-specific manner in glioblastoma (GBM), the most common malignant brain tumor. Additionally, YAP-TRIO signaling activated STAT3, a transcription factor implicated in invasive growth in cancer, suggesting potential for cross-talk with this pathway to exacerbate invasive behavior. Clinically, hyperactivation of YAP, TRIO, and STAT3 gene signatures in GBM were associated with poor survival outcomes in patients. Our findings suggest that the YAP-TRIO-Rho-GTPase signaling network regulates invasive cell spread in both physiological and pathological contexts.
Source: Science Signaling
Institutions: Johns Hopkins University, Johns Hopkins Medicine, Yale University, Centre National de la Recherche Scientifique, Université de Montpellier, Centre de Recherche en Biologie cellulaire de Montpellier, Kennedy Krieger Institute, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: Role of NKCC1 on Brain Tumor Stem Cell Migration After EGF and Slit-2 Stimulation, Systems analysis of phenotypic switch in control of cancer invasion, G5520316217, Analysis of the Signaling and Mechanical Cues Promoting Invasion in Melanoma, Migration of Human Neural Stem Cells In Vitro and In Vivo, G9000320151, A Bioprinted Volumetric Model of Vascularized Glioblastoma, Tumor targeted drug delivery nanoplatform to overcome therapy resistance glioblastoma, Self-Assembling Camptothecin Nanofiber Hydrogels as Adjunct Therapy for Intraoperative Treatment of Malignant Glioma
OpenAlex ID: W4410840955