Objectives/Goals: Develop a precision hydrogel-organoid model to determine how extracellular matrix (ECM) biomechanics drive the malignant transformation of oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC) and identify mechanoresponsive pathways. Methods/Study Population: Patient-derived oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) organoids will be encapsulated in an interpenetrating network hydrogel engineered with tunable stiffness and viscosity to mimic healthy, dysplastic, and cancerous tissue. Organoid growth, morphology, and expression of mechanosensitive markers will be analyzed by imaging and immunostaining. Single-cell RNA sequencing will identify mechanoresponsive markers across genetically diverse patient lines. Targeted inhibitors of EGFR, YAP, and p53 pathways will text whether blocking these signals can prevent mechanics-driven malignant transformation. Results/Anticipated Results: We anticipate that OED organoids in stiffer matrices similar to OSCC tumor stroma will exhibit increased proliferation, altered morphology, and activation of tumorigenic markers similar to OSCC. scRNA-seq is expected to reveal conserved and patient-specific mechanosensitive pathways. Targeted inhibition of these pathways should mitigate mechanics-driven malignant transformation. These outcomes will define molecular mechanisms linking ECM biomechanics to tumor progression and reveal new therapeutic opportunities for early intervention. Discussion/Significance of Impact: This hydrogel-organoid model links patient-specific genetics and ECM biomechanics to tumor progression, enabling controlled studies of how mechanical cues drive malignancy and therapeutic response in a clinically relevant, precision medicine context.
Uddin et al. (Wed,) studied this question.
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