Copper–Collagen Interactions Regulate the Mechanical and Invasive Properties of Tumor Spheroids

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Abstract
Copper is a key trace element with established cytotoxic properties, yet its interactions with the extracellular matrix and their implications for the evolution of 3D culture models remain poorly understood. Here, we study how copper entrapped in collagen can regulate the structural and invasive properties of 3D tumor spheroids. Our findings reveal that copper influences cytoskeletal organization, protrusion dynamics, and epithelial–mesenchymal transitions. Interestingly, we also highlight its dual capacity to either suppress or enhance invasive behavior depending on the context of exposure. These results position copper as a context‐dependent modulator of tumor progression and underscore the importance of dose and timing in determining therapeutic outcomes. By integrating a physiologically relevant 3D model, this study provides new insights into copper–ECM interactions and identifies potential strategies to exploit them for cancer therapy.

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