Publications by authors named "Julia Damiano-Guercio"
Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility.
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- Cell migration relies on actin structures like lamellipodia and filopodia, along with focal adhesions, to facilitate movement; however, Ena/VASP proteins, previously thought to hinder this process, actually enhance it in mouse cell lines.
- The study found that removing Ena/VASP proteins using CRISPR/Cas9 led to less actin assembly in lamellipodia and altered their structure, affecting the geometry and reducing filament numbers and lengths.
- Ena/VASP loss also disrupted microspike formation, impaired integrin-mediated adhesion, and decreased traction forces, indicating these proteins play an essential role in promoting cell migration.
Article Synopsis
- The contractile actin cortex, important for processes like cell division and migration, involves actin, myosin, and various regulatory proteins, but its assembly regulation is unclear.
- Research shows that three formins (ForA, ForE, ForH), regulated by RacE, work together to maintain the structure and function of the actin cortex, with their absence leading to severe defects in cell architecture and functionality.
- Mutants lacking these formins or RacE can move rapidly but struggle with proper cell shape and polarity, indicating that formin-mediated actin assembly is critical for the mechanics of the actin cortex in cells.
Dictyostelium discoideum has proven to be an excellent model to study amoeboid cell migration. During their life cycle, Dictyostelium cells exhibit distinct modes of motility. Individual growth-phase cells explore new territories by random cell migration using the core cell motility machinery, but they can also hunt bacteria by detection and chemotaxis toward the by-product folate.
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