Surface Hydrophobicity Modulates the Key Characteristics of Cancer Spheroids through the Interaction with the Adsorbed Proteins

Three‐dimensional in vitro cancer models have emerged as a promising tool for various cancer‐related applications. However, the limited availability of the in vitro model capable of adequately recapitulating the active interactions between the cancer cells and the surrounding tumor microenvironment (TME) hampers their use for therapeutic applications. Here, it is demonstrated that the proteins adsorbed on the culture substrate significantly influence the characteristics of the cancer cells, thereby suggesting that the modulation of cell–protein interaction can be a powerful tool to construct an advanced cancer model. A series of polymers are prepared for the precise control of the surface hydrophobicity of the culture plate. Cancer cells cultured on the polymers exhibit distinct morphological transitions ranging from monolayer to spheroids with entirely different characteristics depending on the surface hydrophobicity. The poly (cyclohexyl methacrylate) surface of the highest hydrophobicity tested in this study strongly attracts albumin from the media for enhanced adsorption and induces conformational changes in albumin upon binding, leading to the formation of spheroid with the most enriched tumorigenic properties. It is believed that this finding can provide new insights when selecting the experimental strategy to appropriately mimic the complex interplay between the cancer cells and the TME. A series of polymer films with controlled hydrophobicity are synthesized via an initiated chemical vapor deposition process. The surface property‐dependent protein‐adsorption behavior induces significant transition of morphological features and key tumorigenic characteristics of cancer cells, showing the most tumorigenic spheroid on the hydrophobic surface.