Abstract LB211: Genetic complexity in OSCC metastasis: From transcription factors to novel therapeutic targets

Abstract

Abstract Background: The survival of patients with oral cavity squamous cell carcinoma (OSCC) is largely influenced by the extent of locoregional recurrence. Recurrence after standard therapy occurs in about 30% of patients with late-stage OSCC, highlighting the challenge in managing this aggressive form of cancer. The transition of cells from an epithelial to mesenchymal phenotype is a critical event in OSCC invasion and metastasis and is governed by a complex interplay of genes and signaling pathways, with transcription factors such as ZEB1/2 and SNAI1/2 being pivotal players in this process. However, these transcription factors have proven challenging to target therapeutically, and it is likely that additional genes play crucial roles in OSCC pathology. Furthermore, the biology of locoregionally aggressive OSCC cancer cells is poorly understood, and this gap in knowledge is critical to predicting patient outcomes and improving treatment. This lack of understanding underscores the need for further research into identifying the specific molecular mechanisms and genetic factors that drive the locoregional aggressiveness of OSCC. Objective: To evaluate the impact of individual genes on OSCC cell migration, perform a comprehensive analysis of gene-specific effects on cell migration, and develop a valuable platform for the discovery of potential therapeutic targets. Methods: Our lab has created an in vitro model system of “mesenchymal-like” OSCC which exhibits increased migration and chemotherapeutic resistance. Using this model, we generated several cell lines expressing either Cas9 or an activating dCas9. We next transfected genome wide sgRNA libraries. Using a transwell assay platform we are working to identify several key genes necessary for successful cell migration and genes that amplify OSCC cell migratory potential. Results: Our results indicate that OSCC invasion and regional metastasis is a multifaceted process influenced by a network of genes beyond the well-known transcription factors. By subdividing gene expression changes based on E-cadherin protein expression, we are working to therapeutically isolate genes that may be critical during the fleeting transition from an epithelial to mesenchymal phenotype necessary for aggressive OSCC biology. Conclusions: We have identified several genes whose knockout or activation resulted in a significant impact on cell migration, shedding light on potential candidates for therapeutic intervention. The findings from this study will open new avenues for the development of targeted therapies to improve the prognosis of OSCC patients by focusing on previously unexplored genes involved in the invasion and metastatic cascade. Citation Format: Guillermo Flores, Slyn Uaroon, Marisa Buchakjian. Genetic complexity in OSCC metastasis: From transcription factors to novel therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB211.