Trop-2 governs anti-metastatic desmosomal integrity

Abstract Epithelial integrity prevents cancer cell dissemination into distant organs. While the desmosomes, formed by desmosomal proteins such as desmogleins, are critical for epithelial cohesion, their regulation in cancer remains poorly understood. Here, we show that desmogleins (DSG) directly interact with Trophoblast cell surface antigen 2 (Trop-2), a cell adhesion molecule with paradoxical roles in tumor biology. Loss of Trop 2 disrupts this partnership, impairing desmosome formation and intercellular adhesion. Mechanistically, this destabilization drives breast cancer metastasis in vivo through increased matrix metalloproteinase 14 (MMP14, MT1-MMP) production, a key regulator of extracellular matrix degradation and invasion. Our findings show that the Trop-2–DSG2 axis preserves epithelial integrity and suppresses tumor progression, clarifying the function of desmosomes in metastasis.