TROP2 Promotes Tumor Cell Migration through Downregulation of DSG2 Revealed by Super-Resolution Fluorescence Imaging

TROP2 has emerged as a significant biomarker and therapeutic target in various epithelial cancers, owing to its tissue-specific expression and its association with tumor proliferation, invasion, and metastasis. Tumor cell migration is a critical determinant of tumor invasiveness and malignancy, serving as a pivotal factor in prognosis assessment and therapeutic response evaluation. Despite these insights, the molecular mechanisms underpinning TROP2's role in tumor progression─particularly in mediating tumor cell migration─remain incompletely understood. Desmosomes, as essential cell-cell adhesion structures, are integral to maintaining tissue architecture; however, how subtle alterations in their expression and structural organization influence tumor cell adhesion warrants further investigation. In this study, we employed direct stochastic optical reconstruction microscopy (dSTORM) coupled with biochemical approaches to elucidate the mechanism by which TROP2 regulates tumor cell migration via desmosomal cadherin DSG2. Co-localization imaging and coimmunoprecipitation assays confirmed an interaction between TROP2 and DSG2. By establishing TROP2 overexpression and knockdown cell lines, we observed that high TROP2 expression not only downregulated DSG2 levels but also impaired desmosome assembly. These findings were further confirmed at the tissue level. Moreover, we found that TROP2 facilitated tumor cell proliferation and migration by suppressing DSG2 expression and activating EGFR/AKT and FAK downstream signaling pathways. Our findings reveal the molecular mechanism by which TROP2 promotes migration, highlighting the critical role of intercellular junction integrity in cancer progression. These insights provide a foundation for developing targeted therapies against TROP2 and its associated signaling mechanisms in epithelial malignancies.