Space Jam‐Ming: Generating Interstitial Space Using Fragmented Granular GelMA to Investigate Novel Paradigms of Cancer Metastasis

The tumor microenvironment undergoes extensive remodeling during cancer progression, resulting in increased collagen, altered tissue mechanics, and the formation of collagen tracks that permit migration. However, how the extracellular matrix (ECM) regulates cellular plasticity remains less known. Cellular plasticity is essential for successful metastasis, as cells undergo epithelial-to-mesenchymal transition and adherent-to-suspension transition (AST). Studies have begun to use 3D photo-crosslinkable hydrogels, but, unlike in vivo ECM, hydrogel stiffness is inextricably linked to porosity. In this study, we propose a fragmented gelatin methacryloyl (GelMA) scaffold that controls stiffness independently from porosity. When encapsulated as single cells, non-metastatic breast cancer cells do not exhibit growth restriction, whilst pre-engineered metastatic breast cancer cells show altered mechanosensitivity and enhanced migration (p < 0.05). We next study the role of AST in cellular migration and observe similar velocity to invasive metastatic cells. Interestingly, non-metastatic cells showed AST-dependent migration within interstitial spaces, which was enhanced in the stiff scaffold (p < 0.05). AST induction significantly increased Lamin A/C (associated with providing nuclear stability for circulating tumor cells) and reduced nuclear yes-associated protein (YAP) (necessary for cell detachment). Our data highlights the importance of incorporating micro-scale porosity and presents a promising platform for the study of cellular growth and migration.