Project Summary Oral squamous cell carcinoma (OSCC) is the sixth most common epithelial cancer worldwide with 50,000 new cases/year in US. Despite being less frequent, survival rates are relative lower. Clinically, OSCC presents as a necrotic lesion with stiffened borders; surgical resection requires significant tissue loss up to 2 cm surround the lesion, owing to the fact that these tumors are poorly margined and require significant resection to ensure all metastatic disease is removed. Even with aggressive surgical approaches, significant morbidity and mortality is associated with OSCC, and this dramatically reduces patient quality of life. While stiffened borders are a hallmark of the disease, it is unclear to what extent microenvironmental properties, e.g., mechanical changes in extracellular matrix (ECM) stiffness, contribute to tumor progression and invasion. The role of stiffness has been well established in other epithelial tumors, e.g., breast, but our understanding in OSCC is relatively nascent; less than 10 studies have even peripherally addressed the issue. Preliminary data from our groups is the first to demonstrate that a stiffer environment induces epithelial-to-mesenchymal transition (EMT) of oral epithelial cells and that they adopt a more aggressive behavior of invasive OSCC (Matte et al 2019; Moon et al 2023). EMT of these oral tissues might contribute to frequent tumor recurrence observed in patients with excessively stiff tumor margins. Since OSCC is exceedingly invasive, learned behaviors within the stiffened tumor must be remembered and recalled once in softer adjacent oral tissues to facilitate the establishment of secondary disease. Thus, we hypothesize that tumor stiffness induces the acquisition and consolidation of mechanical memory, i.e., EMT and migration, which can be recalled later when the resulting OSCC cells disseminate and contribute to tumor metastasis, invasion, and recurrence. To test this hypothesis, we propose the following specific aims: Specific Aim 1: Elucidate the mechanisms involved in mechanical sensing leading to “memory” acquisition and recall Specific Aim 2: Determine to what extent epigenetic changes in OSCC induce “memory” consolidation