UC San Diego

Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, characterized by poor prognosis. The stiffness of the extracellular matrix (ECM) plays a crucial role in cancer progression by influencing migration and invasion through the epithelial-mesenchymal transition (EMT). This study explores the impact of ECM stiffness on EMT in the less invasive OSCC FaDu cell line. I used polyacrylamide hydrogels with tunable stiffness and functionalized with collagen to enhance biological relevance to mimic the ECM.Our findings reveal that FaDu cells exhibit expression of EMT markers Slug and ZEB1 when cultured on stiff substrates, indicating transcriptional activation and a mesenchymal phenotype. This EMT markers’ expression correlates with higher migration speed observed in cells on stiff substrates, reinforcing a stiffness-induced mesenchymal phenotype. Further analysis showed upregulation of N-cadherin and downregulation of E-cadherin in FaDu cells on stiff substrates, reinforcing the EMT progression. Cytokine profiling indicated upregulation of key cytokines, such as Dkk1 and IL-6, in stiff conditions, which are known to promote EMT and cancer cell motility. Additionally, I identified that FaDu cells have ‘mechanical memory’, where exposure to stiff conditions enabled them to maintain mesenchymal traits even after transitioning to softer environments. These results highlight the significance of ECM stiffness in regulating EMT and cancer cell behavior, which could potentially be used for developing therapeutic targets to inhibit OSCC progression and metastasis.