Abstract 3873: Uncovering key regulators of OSCC invasion: A pathway to novel therapeutic strategies

Abstract Recurrence and metastasis are the primary drivers of poor prognosis in patients with Oral Squamous Cell Carcinoma (OSCC), even after aggressive surgical interventions. To uncover the genetic regulators of OSCC invasion and migration, we conducted a first-of-its-kind genome-wide CRISPR screen. This screen identified several key players involved in epithelial-mesenchymal transition (EMT), a critical process in tumor progression and metastasis. Among the top hits was EDIL3, a gene that codes for a secreted protein that promotes EMT and chemotherapy resistance by interacting with integrin receptors in the extracellular matrix. Though previously implicated in other cancers, EDIL3’s role in OSCC has not been described. Additionally, our screen highlighted NISCH as the top anti-invasion hit, a gene whose expression is positively correlated with survival in head and neck cancers, including OSCC. NISCH appears to inhibit EDIL3-driven invasion by interfering with integrin-mediated signaling, potentially via a FAK and WNT5a-dependent mechanism. Current work is focused on characterizing EDIL3 and NISCH knockouts to validate their roles in OSCC migration and invasion. Functional assays such as spheroid formation and wound healing experiments are being performed to assess the impact of these knockouts on tumor cell behavior. Additionally, we are investigating FDA-approved drugs targeting these pathways to explore immediate translational potential. This research represents a novel approach to identifying genetic drivers of cancer metastasis and offers promising avenues for the development of targeted therapies for OSCC to reduce recurrence and improve patient outcomes. Citation Format: Guillermo Flores, Slyn Uaroon, Juan A. Raygoza Garay, Marisa R. Buchakjian. Uncovering key regulators of OSCC invasion: A pathway to novel therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3873.