Browsing by Author "Lang, Julie"

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    Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents
    (bioRxiv, 2024-09-07) Villagomez, Fabian R.; Lang, Julie; Nunez-Avellaneda, Daniel; Behbakht, Kian; Dimmick, Hannah L.; Webb, Patricia; Nephew, Kenneth P.; Neville, Margaret; Woodruff, Elizabeth R.; Bitler, Benjamin G.; Anatomy, Cell Biology and Physiology, School of Medicine
    During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.
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    Claudin-4 Stabilizes the Genome via Nuclear and Cell-Cycle Remodeling to Support Ovarian Cancer Cell Survival
    (American Association for Cancer Research, 2025) Villagomez, Fabian R.; Lang, Julie; Nunez-Avellaneda, Daniel; Behbakht, Kian; Dimmick, Hannah L.; Webb, Patricia G.; Nephew, Kenneth P.; Neville, Margaret; Woodruff, Elizabeth R.; Bitler, Benjamin G.; Anatomy, Cell Biology and Physiology, School of Medicine
    High-grade serous ovarian carcinoma is marked by chromosomal instability, which can serve to promote disease progression and allow cancer to evade therapeutic insults. The report highlights the role of claudin-4 in regulating genomic instability and proposes a novel therapeutic approach to exploit claudin-4-mediated regulation.