Cellular mechanosensing and mechanotransduction dictate the manner in which cancer cells perceive and react to their physical microenvironment. Cancer spheroids, self-organized 3D aggregates of tumor cells, offer a unique platform to investigate these processes at supracellular scales, bridging single-cell mechanobiology with tissue-level behaviors. We developed spheroid models using breast and ovarian cancer cells to dissect how adhesion networks, supracellular mechanics, and microenvironmental stiffness shape tumor progression. In breast cancer spheroids, differential reliance on E-cadherin versus integrin β1 produced strikingly distinct invasion modalities: E-cadherin-mediated aggregates favored cohesive spreading, while integrin-enriched spheroids exhibited enhanced invasiveness. These models emphasize how adhesion programs dictate collective versus scattering migration modes. Extending this approach to ovarian cancer, we asked whether tumor cells retain a “mechanical memory” of their primary stiffness environment during metastatic dissemination. By priming cells on substrates of defined stiffness and assembling them into spheroids, we found that soft-primed spheroids formed cohesive structures with supracellular actin cages, whereas stiff-primed spheroids exhibited lumen-like architectures and elevated invasion capacity. Functional assays in collagen gels confirmed that stiff priming accelerated spheroid spreading and invasion, highlighting that metastatic potential is not only a function of the current microenvironment but also of past mechanical history encoded at the spheroid level. Together, these studies demonstrate that spheroid models provide powerful tools for unraveling how cancer cells integrate mechanical cues into adhesion dynamics, supracellular organization, and long-term invasive behaviors. By combining advanced imaging, force mapping, and functional assays, our work highlights the importance of 3D spheroids as versatile mechanobiology models with broad implications for understanding cancer progression and therapeutic resistance.
Shin et al. (Sun,) studied this question.